Absorbable Medical Devices Based on Novel Films and Foams Made From Semi-Crystalline, Segmented Copolymers of Lactide and Epsilon-Caprolactone Exhibiting Long Term Absorption Characteristics

ABSTRACT

Absorbable medical devices based on novel foams and films made from semi-crystalline, segmented copolymers of lactide and epsilon-caprolactone exhibiting long term absorption characteristics are disclosed. Also disclosed are methods of producing said foams and films, and useful polymer solutions.

FIELD OF THE INVENTION

This invention relates to novel semi-crystalline, block copolymers oflactide and epsilon-caprolactone for long term absorbable medicalapplications, in particular, medical devices such as surgical foams andfilms.

BACKGROUND OF THE INVENTION

Synthetic absorbable polyesters are well known in the art. The termsabsorbable, bioabsorbable, bioresorbable, resorbable, biodegradable areused herein interchangeably. The open and patent literature particularlydescribe polymers and copolymers made from glycolide, L(−)-lactide,D(+)-lactide, meso-lactide, epsilon-caprolactone, p-dioxanone, andtrimethylene carbonate.

A very important aspect of any absorbable medical device is the lengthof time that its mechanical properties are retained in vivo. Forexample, in some surgical applications it is important for the device toretain strength for a considerable length of time in order to allow thebody the time necessary to heal while performing its desired function.Such slow healing situations include, for example, diabetic patients orbodily areas having poor or diminished blood supply. Absorbable longterm sutures are known and have been made from conventional polymers,primarily from lactide. Examples include a braided suture made from ahigh-lactide, lactide/glycolide copolymer. Those skilled in the art willappreciate that monofilament and multifilament absorbable sutures existin the art and that short term and long term absorbable sutures alsoexist in the art. Long term functioning may be described as retaining acertain amount of mechanical integrity in vivo beyond 10 to 12 weekspost-implantation.

Medical devices in the form of polymeric foams or films are known in theart. What does not presently exist is an absorbable polymer that can bemade into a foam that is soft enough to exhibit mechanical elasticity toprovide both spring-back when compressed and superior handlingcharacteristics to the surgeon, yet maintain its mechanical propertiespost-implantation to function effectively long term while fullyabsorbing. There then remains the problem of providing such a polymerthat can meet these needs. There is also a need for an absorbablesurgical foam made from such a polymer. Absorbable foams generally comein two basic forms, open cell structures and closed cell structures.Open cell foams are particularly advantageous for tissue engineeringapplications requiring cell ingrowth. Buttress designs of various sortshave been described for use with mechanical surgical staplers, but animplantable absorbable foam buttress has yet to be provided that meetslong term needs.

Foam formation from polymeric materials has been described by variousresearchers over the years. For instance, foams have been made by meltprocesses such as extrusion with blowing agents and utilizingsupercritical carbon dioxide.

For example, the use of supercritical carbon dioxide in making foams isdisclosed in “Formation and size distribution of pores inpoly(ε-caprolactone) foams prepared by pressure quenching usingsupercritical CO₂”, Karimi, et. al, J. of Supercritical Fluids 61 (2012)175-190. The use of supercritical carbon dioxide in making foams is alsodisclosed in “Supercritical Carbon Dioxide: Putting the Fizz intoBiomaterials”, Barry, et. al, Phil. Trans. R. Soc. A 2006 364, 249-261.

Lyophilization is well known in the art and has been used to preparefoams from synthetic absorbable materials. This process is not withoutdifficulties, however. The polymer to be lyophilized must be soluble inthe selected solvent, and there are only a limited number of solventsthat are suitable for the lyophilization process. The freezing point ofa successful solvent needs to be above that of a reasonable shelf andcondenser temperature (˜−70° C.), and low enough to convenientlydissolve the resin to be lyophilized. Moreover, the vapor pressure atlow temperature needs to be high enough so that the solvent can besublimated from the frozen state at a reasonable enough rate. Typicalsolvents conventionally used in lyophilization processes include water,1,4-dioxane, DMSO, DMF, and certain alcohols. Most absorbable polyestersare hydrophobic in nature while the solvents suitable for lyophilizationtend to be polar in nature; this creates solubility issues as it is therare absorbable polymer that can be dissolved in an appropriatelyophilizing solvent.

The final architecture of a polymeric foam made by lyophilizationdepends on a number of factors, including the polymer concentration inthe solvent. Higher mechanical properties often correlate with the bulkdensity of the foam; high densities then require higher concentrationsof the dissolved polymer; for example, 10 weight percent initial solidsdissolved in the lyophilizing solvent versus 3 weight percent initialsolids. Although a given polymer may be considered soluble in a solvent,it may not be soluble at the high concentrations that may be needed forfoam medical devices. Even those absorbable polymers that are soluble insolvents suitable for lyophilization may present another difficultyarising from the phenomena of premature gel formation. Premature gelformation is known to interfere with the making of homogeneous foams, asis required. Premature gelation is particularly challenging in highconcentration solutions. It is believed that the gelation phenomena maybe due to inter- and intra-chain molecular associations, similar to whatmight occur during crystallization in solids, although not as strongly.Once gelation takes place in a lyophilizing polymer solution, it is verydifficult for polymer chains to possess the mobility they need duringthe phase separation that must occur as pure solvent (that is solventwithout dissolved polymer) crystallizes. Individual chains are “fixed”in place and cannot disentangle to join a solvent/polymer phase of everincreasing polymer concentration.

It has been noted that lyophilizing solutions having higher polymerconcentrations may be achieved by lowering the molecular weight of thegiven polymer, but this has the disadvantage of lowering the mechanicalproperties of the resultant foam, to unacceptable levels for mostsurgical applications.

Absorbable polymeric foams to be used in medical applications musttypically exhibit dimensional stability, that is, the foams must notdeform while undergoing additional, conventional post-processingtreatments such as ethylene oxide sterilization, transportation,warehouse storage, and such. This is often a challenge when working withpolymers possessing low glass transition temperatures since molecularmobility is enhanced, thereby readily allowing warping, shrinking andother distortions. The crystallization of the polymer constituting thefoam is one means of achieving dimensional stability. It should be notedhowever that a polymer resulting in too high a level of crystallinity inthe foam may result in a final article which is too stiff for a givensurgical application. For example, the level of “spring back” may beinadequate. Thus, important mechanical properties may be influenced notonly by the polymer itself (T_(g), etc.) but also by the polymermorphology that develops in the final product, again greatly influencedby the polymer and its thermal history. The level of crystallinity inthe resin prior to attempted dissolution is also important in low T_(g)resins. If the crystallinity is too low the resin pellet (or groundresin)_may begin to stick to itself during storage or transportation ifexposed to even the slightest elevated temperatures, for example 20° C.The once divided, free-flowing polymer granules gradually aggregate intoa large brick-like mass. If the crystallinity of the resin is too high,difficulties may be experienced during attempts to dissolve the resin inthe selected solvent; that is, the resin may not properly dissolve.

The lyophilization process is demanding in that it is difficult toproduce a suitable product in a robust fashion. If the polymer does notreadily dissolve, if it tends to gel too quickly, if it cannot maintaindimensional stability during the process (as well as later during EOsterilization or during transportation), or if the solvent cannot beadequately removed, a suitable foam will not result.

Of course being able to make an absorbable polymeric foam with anappropriate architecture does not complete the challenge; one needs toprovide a foam with appropriate ester chemistry to achieve anappropriate hydrolysis profile post-implantation. Retention ofmechanical properties for a number of long term surgical applications iscritical in slow to heal patients or in slow to heal bodily tissue.Finally, the polymer must still be absorbable; that is, slowly hydrolyzeto be removed by the body from the surgical site.

The polymer must then possess certain solubility and crystallizationcharacteristics, as well as certain mechanical and hydrolysisproperties, if it is to be suitable for fabricating surgical foamproducts by the lyophilization method.

The use of some absorbable synthetic polyesters for foam formation vialyophilization processes is known and disclosed in the art. Examplesinclude for example, U.S. Pat. No. 5,468,253, Bezwada, et al.,“Elastomeric Medical Device”, filed on Jan. 21, 1993 and issued on Nov.21, 1995, which discloses medical devices or components for medicaldevices formed from bioabsorbable elastomers comprising a randomcopolymer of from about 30 to about 70 weight percent of: a)ε-caprolactone, trimethylene carbonate, and ether lactone, or a mixtureof these, and b) the balance being substantially glycolide,para-dioxanone, or a mixture of these. U.S. Pat. No. 5,468,253 furtherdiscloses bioabsorbable foams made from the elastomers.

U.S. Pat. No. 6,355,699, Vyakarnam, et al., “Process for ManufacturingBiomedical Foams” filed on Jun. 30, 1999 and issued on Mar. 12, 2002discloses an improved lyophilization process for forming biocompatiblefoam structures.

The ϵ-caprolactone/glycolide copolyesters described by Vyakarnam et al.are directed towards elastomeric materials (see col 5, lines 32 to 36).Their one-step, one-pot polymerization process method tends to producepolymers that exhibit a random distribution of monomer repeat units,while the compositions of the Vyakarnam et al. polyesters made by asequential addition method, which can be used to produce clearlynon-random sequence distributions, are outside the scope of the presentinvention. In general, the substantially random copolymers of Bezwada,et al and Vyakarnam et al. are quite soluble in at least onelyophilizing solvent, 1,4-dioxane, and only form the undesired gelsafter an extended period of time. This last characteristic is valuablefrom a manufacturing standpoint in that it allows significant leeway inprocessing times. An undesirable characteristic, however, of the randomε-caprolactone/glycolide copolyesters described by Bezwada et al. isthat their copolymers are able achieve only low levels of crystallinity.This is a very important characteristic because these copolymers possessrelatively low glass transition temperatures and thus do not have therequired crystallinity to achieve dimensional stability. During heattreatment (annealing) to purposefully mature the polymer morphology(possibly increase crystallinity levels), it was found that undesirableshrinkage occurred to varying degrees; reliable treatments could not befound to robustly produce acceptable foam product.

Additionally it has been found that lower levels of crystallinity resultin a more rapid loss of mechanical properties due to faster hydrolysisof the polymer chains.

Donners et al. in commonly-assigned, co-pending U.S. patent applicationSer. No. ______ (Attorney Docket No. ETH5834) filed on evendate herewithand incorporated by reference, overcomes these limitations of lowcrystallinity by preparing Cap/Gly polymers utilizing a staged additionprocess thus creating glycolide end block capped polymers. This resultsin retaining a longer functional performance over time and betterdimensional stability. However these kind of polymers are only solublein sufficient concentrations in 1,4-dioxane within a limited range. Inaddition, the introduction of end blocks, while desirable forperformance of the resulting device, leads to more rapid gel formation.

Accordingly, all attempts in the prior art to produce an acceptablemedical foam from a gelled polymeric lyophilizing solution [changingfreezing rate, drying temperature, etc.] did not result in a foam, letalone a foam useful for medical purposes. The resultant product mayappear as a distorted film, not unlike the shape of a potato chip. Thus,specific processing conditions are needed to obtain a thoroughly frozensolution before gel formation occurs in order to achieve a proper foam.

Bioabsorbable films and film formation from bioabsorbable polymericmaterials have also been described by various researchers over theyears, e.g., U.S. Pat. No. 7,943,683 B2, “Medical Devices ContainingOriented Films of Poly-4-hydroxybutyrate and Copolymers”; U.S. Pat. No.8,030,434 B2, “Polyester Film, Process for Producing the Same and UseThereof”; U.S. Pat. No. 4,942,087A, “Films of Wholly Aromatic Polyesterand Processes for Preparation Thereof”; U.S. Pat. No. 4,664,859A,“Process for Solvent Casting a Film”; and, U.S. Pat. No. 5,510,176A,“Polytetrafluoroethylene Porous Film”. Various conventionalmethodologies are known and exist to produce polymeric films. Theyinclude melt extrusion, solvent casting, and compression molding. Notall polymers can be easily converted to film products; additionally,different conversion techniques have different challenges. In the caseof melt extrusion, the resin must be thermally stable, exhibiting anappropriate melt viscosity, i.e., not too low so as to cause “dripping”and not too high so as to develop excessively high pressures in theextruder, causing instability and non-uniform results. In the case ofresins possessing low glass transition temperatures, the dimensionalstability of the films made therefrom may be very low if the polymermorphology includes some chain orientation. This is a great drivingforce for shrinkage and distortion. To circumvent dimensionalinstability difficulties, the development of a certain amount ofcrystallinity in the film is advantageous. The rate of crystallizationis important in establishing a robust film extrusion process, while theoverall level of crystallinity is important in achieving dimensionalstability and good mechanical properties. It is known that too low acrystallinity level will result in films which may distort upon ethyleneoxide sterilization or upon exposure to even mildly elevatedtemperatures during processing, transportation, or storage. In a fewsurgical applications it is desirable for the final films to be strongwith appropriate tear resistance, yet pliable enough to possess goodhandling characteristics.

An absorbable polymer used to manufacture films must possess certainmelt and thermal properties, certain crystallization characteristics, aswell as certain mechanical and hydrolysis properties, if it is to besuitable for fabricating surgical film products by the melt extrusionprocess. In the case of films made by solution casting, the polymerresin needs to possess appropriate solubility in a suitable solvent.Suitable solvents advantageously have an appropriate vapor pressurecurve leading to suitable evaporation rates, and are generallynon-toxic. The polymer must then possess certain solubility andcrystallization characteristics, as well as certain mechanical andhydrolysis properties, if it is to be suitable for fabricating surgicalfilm products by a solvent casting process.

Electrostatically spun nonwovens from absorbable polymeric materials areknown in the art and have been described by various researchers. See forexample U.S. Pat. No. 7,332,050 B2, “Electronic Spinning Apparatus, anda Process of Preparing Nonwoven Fabric Using the Same”; U.S. Pat. No.7,934,917 B2. “Apparatus for Electro-Blowing or Blowing-AssistedElectro-Spinning technology”; and, U.S. Pat. No. 8,636,942 B2, “NonwovenFabric and Process for Producing the Same”. One of the challengespresent with electrostatically spun absorbable polymeric nonwovens isthat the polymeric material must possess a number of particularcharacteristics. The polymer must possess adequate solubility in anappropriate solvent to create a suitable spinning dope. The rate ofcrystallization of the polymer must be appropriate to allow for a robustmanufacturing process. The level of crystallinity that can be ultimatelydeveloped in the nonwoven fabric made of the polymer must be high enoughso as to provide the fabric with appropriate dimensional stability. Thelevel of crystallinity developed also influences the mechanicalproperties of the fabric. As pointed out earlier, crystallinity levelsof the resin can be too high, making solubilization of the resindifficult. Crystallinity levels can also be too high in the fabric, madetherefrom, negatively affecting mechanical properties and biologicalperformance. There is a need in this art for novel polymers that providesufficient mechanical properties long-term, post-implantation; and,novel polymers having glass transition characteristics that provide forsoftness in finished goods.

Melt-blown nonwoven constructs from absorbable polymeric materials arealso known in this art. See for example U.S. Pat. No. 4,769,279A, “LowViscosity Ethylene Acrylic Copolymers for Nonwovens”; U.S. Pat. No.8,278,409 B2, “Copolymers of Epsilon-Caprolactone and Glycolide for MeltBlown Nonwoven Applications”; and, U.S. Pat. No. 8,236,904 B2,“Bioabsorbable Polymer Compositions Exhibiting Enhanced Crystallizationand Hydrolysis Rates”. One of the challenges with these constructs isthat the polymeric material must possess a number of characteristics,including adequate melt viscosity, appropriate rates crystallization,and provide appropriate crystallinity in the finished goods. Thepolymers need to provide sufficient mechanical properties to themelt-blown constructs long-term, post-implantation, and also provide forsoftness in finished goods.

Accordingly, there is a need in the art for novel absorbable polymericfoams, films and nonwovens to be used in medical applications.

Specifically in the case of absorbable foams, there is a need to provideretention of mechanical properties post-implantation for extendedperiods of time, such 64 days or longer. Additionally, there is need toprovide foams with improved dimensional stability to avoid warping,shrinking and other distortions during sterilization, storage,transportation, or an exposure to slightly elevated temperatures.Furthermore, there is a need to provide absorbable foams possessingappropriate stiffness, being neither too soft nor too hard, to allowgood “spring-back” upon compression; this requires a proper range ofcrystallinity and T_(g).

Further, there is a great need for an absorbable polymer that possesseshigh solubility characteristics in certain key solvents to avoidgelation during foam formation using the lyophilization method ofmanufacture.

Finally, there exists a need to provide an absorbable polymer possessingan adequate crystallization rate and the ability to achieve an adequatecrystallization level so as to be able to form dimensionally stablefoams by the lyophilization process, to form dimensionally stable filmsby a melt extrusion process, and to form dimensionally stable nonwovenfabrics by either electrostatic spinning or by melt blown processes.

SUMMARY OF THE INVENTION

Novel films and foams made from semi-crystalline, block copolymers oflactide and epsilon-caprolactone for long term absorbable medicalapplications are disclosed. The semicrystalline absorbable segmentedcopolymers, have repeating units of polymerized lactide and polymerizedepsilon-caprolactone. The mole ratio of polymerized lactide topolymerized epsilon-caprolactone is between about 60:40 to about 75:25,and the copolymers possess a first heat T_(g) as determined bydifferential scanning calorimetry at a scan rate of 10° C. per minute,equal to or less than 0° C., and a crystallinity level of about 25percent to about 50 percent, as measured by wide angle X-raydiffraction.

Another aspect of the present invention is a method of making anabsorbable foam by a melt process. The method has the steps of:

-   -   A. providing an absorbable polymer comprising a semicrystalline        absorbable segmented copolymer, said copolymer comprising        repeating units of polymerized lactide and polymerized        epsilon-caprolactone, wherein the mole ratio of polymerized        lactide to polymerized epsilon-caprolactone is between about        60:40 to about 75:25, said copolymer having a first heat Tg, as        determined by differential scanning calorimetry at a scan rate        of 10° C. per minute, equal to or less than 0° C., and a        crystallinity level of about 20 to about 50 percent, as measured        by wide angle X-ray diffraction, said copolymer having a melt        temperature;    -   B. heating the copolymer above its melt temperature to form a        melt;    -   C. introducing a suitable blowing agent (chemical or physical)        into the melt; and,    -   D. enabling the gas produced from the blowing agent to expand        within the melt to form an absorbable foam.

Yet another aspect of the present invention is a method of making anabsorbable foam by a melt process, having the steps of:

-   -   A. providing an absorbable polymer comprising a semicrystalline        absorbable segmented copolymer, said copolymer comprising        repeating units of polymerized lactide and polymerized        epsilon-caprolactone, wherein the mole ratio of polymerized        lactide to polymerized epsilon-caprolactone is between about        60:40 to about 75:25, said copolymer having a first heat Tg, as        determined by differential scanning calorimetry at a scan rate        of 10° C. per minute, equal to or less than 0° C., and a        crystallinity level of about 20 to about 50 percent, as measured        by wide angle X-ray diffraction, said copolymer having a melt        temperature;    -   B. transferring the said absorbable polymer to the hopper of a        melt extruder outfitted with a profile die, with a barrel        outfitted with a gas injection port, and die heated to a        temperature within the range of about 10° C. above the melt        temperature of said absorbable polymer to about 270° C. to form        a melt;    -   C. extruding said absorbable polymer through said profile die,        while injecting into the melt through the gas injection port a        gas selected from the group of carbon dioxide, nitrogen, helium,        and argon, resulting in a foam; and,    -   D. collecting said foam at a rate to result in a foam thickness        between about 0.1 mils and 50 mils.

A further aspect of the present invention is a method of making anabsorbable foam by a melt process, comprising the steps of:

-   -   A. providing an absorbable polymer comprising a semicrystalline        absorbable segmented copolymer, said copolymer comprising        repeating units of polymerized lactide and polymerized        epsilon-caprolactone, wherein the mole ratio of polymerized        lactide to polymerized epsilon-caprolactone is between about        60:40 to about 75:25, said copolymer having a first heat Tg, as        determined by differential scanning calorimetry at a scan rate        of 10° C. per minute, equal to or less than 0° C., and a        crystallinity level of about 20 to about 50 percent, as measured        by wide angle X-ray diffraction, said copolymer having a melt        temperature;    -   B. transferring the said absorbable polymer in combination with        a solid blowing agent to the hopper of a melt extruder outfitted        with a profile die, and die heated to a temperature within the        range of about 10° C. above the melt temperature of said        absorbable polymer to about 270° C.;    -   C. extruding said absorbable polymer through said profile die,        resulting in a foam; and,    -   D. collecting said foam at a rate to result in a foam thickness        between about 0.1 mils and 50 mils.

Still yet another aspect of the present invention is a method of makingan absorbable foam by a lyophilization process. This process has thesteps of:

-   -   A. providing an absorbable polymer comprising a semicrystalline        absorbable segmented copolymer, comprising repeating units of        polymerized lactide and polymerized epsilon-caprolactone,        wherein the mole ratio of polymerized lactide to polymerized        epsilon-caprolactone is between about 60:40 to 75:25, said        copolymer having a first heat Tg as determined by differential        scanning calorimetry at a scan rate of 10° C. per minute, equal        to or less than 0° C., and a crystallinity level of about 20 to        about 50 percent, as measured by wide angle X-ray diffraction;    -   B. dissolving a sufficient quantity of the copolymer in a        suitable solvent to form a lyophilizing solution;    -   C. pouring at least a part of the solution into a suitable mold;        and,    -   D. subjecting the solution in the mold to a lyophilizing process        to form an absorbable foam.

An additional aspect of the present invention is a lyophilizingsolution. The solution has a solvent selected from the group consistingof 1,4-dioxane, trioxane, a mixture of at least 90 weight percent1,4-dioxane and no more than 10 weight percent water, a mixture of atleast 90 weight percent 1,4-dioxane and no more than 10 weight percentof an organic alcohol having a molecular weight of less than 1,500Daltons. In addition, the lyophilizing solution of the present inventionhas about 3 wt. % to about 35 wt. % of a semicrystalline absorbablesegmented copolymer, which possesses repeating units of polymerizedlactide and polymerized epsilon-caprolactone, wherein the mole ratio ofpolymerized lactide to polymerized epsilon-caprolactone is between about60:40 to 75:25, said copolymer having a first heat Tg as determined bydifferential scanning calorimetry at a scan rate of 10° C. per minute,equal to or less than 0° C., and a crystallinity level of about 20 toabout 50 percent, as measured by wide angle X-ray diffraction.

Yet another additional aspect of the present invention is a method ofmaking an absorbable film by melt processing. This process has thefollowing steps:

-   -   A. providing an semicrystalline absorbable segmented copolymer,        comprising repeating units of polymerized lactide and        polymerized epsilon-caprolactone, wherein the mole ratio of        polymerized lactide to polymerized epsilon-caprolactone is        between about 60:40 to 75:25, said copolymer having a first heat        Tg as determined by differential scanning calorimetry at a scan        rate of 10° C. per minute, equal to or less than 0° C., and a        crystallinity level of about 20 to about 50 percent, as measured        by wide angle X-ray diffraction, said copolymer having a melt        temperature;    -   B. transferring the said absorbable polymer to the hopper of a        melt extruder outfitted with a slit die, with a barrel and die        temperature within the range of about 10° C. above the melt        temperture of the said absorbable polymer and about 270° C.;    -   C. extruding said absorbable polymer through said slit die,        resulting in a film; and,    -   D. drawing the film between about 0.8× to about 10× to form a        film having a thickness between about 0.1 and 50 mils.        Yet another aspect of the present invention is a method of        making an absorbable film by a solution process. The method has        the steps of:    -   A. providing an absorbable polymer comprising a semicrystalline        absorbable segmented copolymer, said copolymer comprising        repeating units of polymerized lactide and polymerized        epsilon-caprolactone, wherein the mole ratio of polymerized        lactide to polymerized epsilon-caprolactone is between about        60:40 to about 75:25, said copolymer having a first heat Tg, as        determined by differential scanning calorimetry at a scan rate        of 10° C. per minute, equal to or less than 0° C., and a        crystallinity level of about 20 to about 50 percent, as measured        by wide angle X-ray diffraction;    -   B. dissolving a sufficient quantity of the copolymer in a        suitable solvent to form a polymer solution;    -   C. pouring at least a part of the solution into a suitable mold        or dispensing the polymer solution onto a conveying surface;        and,    -   D. allowing the solvent to be removed from the polymer solution        to form an absorbable film.

These and other aspects and advantages of the present invention willbecome more apparent from the following description and accompanyingdrawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a plot of isothermal crystallization kinetics, as measured byDifferential Scanning calorimetry, of the final inventive copolymers ofExamples 1 and 3A.

FIG. 2 is histogram of sequence distribution results for the finalinventive copolymers of Examples 1, 2A, 2B, 3A and 3B as measured by ¹³CNMR.

FIG. 3A is a photograph of three foam strips from Example 7 (10% w/wconcentration) prior to exposure to a pH 7.27 phosphate bufferedsolution at 37° C.

FIG. 3B is a photograph of three foam strips from Example 7 (10% w/wconcentration) after exposure to a pH 7.27 phosphate buffered solutionat 37° C. for 28 days.

FIG. 3C is a photograph of three foam strips from Example 7 (10% w/wconcentration) after exposure to a pH 7.27 phosphate buffered solutionat 37° C. for 64 days.

FIG. 4A is a photograph of three foam strips from Example 8 (10% w/wconcentration) prior to exposure to a pH 7.27 phosphate bufferedsolution at 37° C.

FIG. 4B is a photograph of three foam strips from Example 8 (10% w/wconcentration) after exposure to a pH 7.27 phosphate buffered solutionat 37° C. for 28 days.

FIG. 4C is a photograph of three foam strips from Example 8 (10% w/wconcentration) after exposure to a pH 7.27 phosphate buffered solutionat 37° C. for 64 days.

FIG. 5A is a photograph of three foam strips from Example 8 (20% w/wconcentration) prior to exposure to a pH 7.27 phosphate bufferedsolution at 37° C.

FIG. 5B is a photograph of three foam strips from Example 8 (20% w/wconcentration) after exposure to a pH 7.27 phosphate buffered solutionat 37° C. for 28 days.

FIG. 5C is a photograph of three foam strips from Example 8 (20% w/wconcentration) after exposure to a pH 7.27 phosphate buffered solutionat 37° C. for 64 days.

FIG. 6A is a photograph of three foam strips from Example 9 (10% w/wconcentration) prior to exposure to a pH 7.27 phosphate bufferedsolution at 37° C.

FIG. 6B is a photograph of three foam strips from Example 9 (10% w/wconcentration) after exposure to a pH 7.27 phosphate buffered solutionat 37° C. for 28 days.

FIG. 6C is a photograph of three foam strips from Example 9 (10% w/wconcentration) after exposure to a pH 7.27 phosphate buffered solutionat 37° C. for 64 days.

FIG. 7A is a photograph of three foam strips from 36/64 Caprolactone andGlycolide Comparator (10% w/w concentration) prior to exposure to a pH7.27 phosphate buffered solution at 37° C.

FIG. 7B is a photograph of three foam strips from 36/64 Caprolactone andGlycolide Comparator (10% w/w concentration) after exposure to a pH 7.27phosphate buffered solution at 37° C. for 28 days; each strip iscontained in a vial.

FIG. 7C is a photograph of three foam strips from 36/64 Caprolactone andGlycolide Comparator (10% w/w concentration) after exposure to a pH 7.27phosphate buffered solution at 37° C. for 64 days.

FIG. 8 is a photograph of two foam strips from 36/64 Caprolactone andGlycolide Comparator with endblocks (10% w/w concentration): The topfoam was made using a lyophilization recipe with a “quench” freeze,allowing the solution to be cooled quickly so it freezes before a gelcan form. The bottom foam was made without the quench step, whichresulted in a failed foam that a) had high residual 1,4 dioxane levels,and b) had a warped “potato-chip”-like appearance.

FIG. 9 is a photograph of a failed foam strip prepared as a 4×4 inchsheet from 36/64 Caprolactone and Glycolide Comparator with endblocks(10% w/w concentration). This foam strip was made without using a“quench” freeze.

DETAILED DESCRIPTION OF INVENTION

As used herein, and for clarity purposes, a number of terms will bedefined. A random (copolyester) copolymer is defined as a copolyesterhaving a sequence distribution of the monomer moieties along the chainthat is at least as random as a copolymer of that overall compositionmade from lactone monomers or hydroxy acids in which all the monomersare added in a single step to the polymerization reactor, as governed byreactivity ratio considerations at the time of the polymerization.

Statistical copolymers are copolymers in which the sequence of monomerresidues follows a statistical rule. If the probability of finding agiven type monomer residue at a particular point in the chain is equalto the mole fraction of that monomer residue in the chain, then thepolymer may be referred to as a “truly random copolymer”. In a randomcopolymer, the sequence distribution of monomeric units followsBernoullian statistics.

Truly random copolymers are difficult to find due to the complicationsof the phenomena of monomer reactivity ratios. Although the monomers maybe added to a batch reactor in a single step, there may be a slightpropensity of one monomer adding to the growing chain over anothermonomer. This is discussed further below in this specification.

To form a random copolymer, in a batch polymerization process, themonomers are generally added to the batch reactor in a single step. In acontinuous polymerization process, the monomers are added to thecontinuous reactor in a substantially constant composition.

A segmented (copolyester) copolymer on the other hand possesses anon-random sequence distribution beyond what would be expected based onreactivity ratio considerations that is less random than a randomcopolymer.

When the sequence length of a given monomer starts to get large, itbegins to approach a blocky structure. A “block copolymer” can bemulti-block in nature, tetrablock, triblock or diblock, depending on thenumber of different chemical blocks.

A block copolymer that is a “diblock copolymer” might have a structurecontaining two different chemical blocks and is then referred to as anA-B block copolymer. If a triblock copolymers has one monomer sequence,A, at its ends and a second, B, in its interior, it might be referred toan A-B-A block copolymer.

A known technique to produce a non-random sequence distribution inring-opening polymerizations is the method of adding different monomerfeeds to the reactor in stages. One might add an amount of monomer B tothe reactor with a monofunctional initiator. A polymer is formed made ofonly B sequences. A second monomer, A, is then added to the reactor; thecopolymer thus formed might then be an A-B block copolymer. Alternately,if a difunctional initiator is used at the start of the polymerization,the copolymer thus formed might then be an A-B-A block copolymer.

To help in characterizing the “blockiness” of the sequence distributionof a copolymer, Harwood (reference: Harwood, H. J.; Ritchey, W. M.Polymer Lett. 1964, 2, 601) disclosed a “run number” concept. For acopolymer made up of polymerized “A” repeat units and polymerized “B”repeat units, the corresponding run numbers reflect the average chainsequence length for the individual “monomers”. In looking down thechain, every time an A unit was encountered, a counter was activated.Every time another A unit was observed, the counter was increased byone; the counter was stopped as soon as a B unit was reached. When theentire chain is sampled and the work completed on the rest of the resin,an average value can be established for the Harwood run number for the“A” unit. The same can be done for “B”. Statistical treatments haveshown that for a theoretically random copolymer of AB molar composition,the Harwood run number for each of the components can be calculatedbased on the following equations:

HRN_(A)=1+([A]/[B]) and HRN_(B)=1+([B]/[A])  (1)

where HRN_(A) and HRN_(B) are the Harwood Run Numbers for repeat units Aand B, respectively, [A] and [B] are the molar fractions of repeat unitsA and B, respectively.

Thus a 20/80 AB random copolymer made up of A and B units is expected tohave Harwood run numbers of 1.25 and 5.0 for A and B, respectively. Inthe case of non-random copolymers, it is possible to have a copolymer ofthe same 20/80 composition with a Harwood run number for the A componentmuch higher than the 1.25 value displayed in the random copolymer, forinstance 1.5 or 3. This is clearly indicative of a propensity of “A”units to be together, i.e., a blocky sequence distribution.

In a copolymerization, the monomers may not be sequenced exactlyrandomly due to a phenomenon in which there is a great propensity of“monomer 1” to add to a growing chain terminated in a “monomer 1 repeatunit” or a great propensity of monomer 1 to add to a growing chainterminated in a “monomer 2 repeat unit”. The concept of reactivityratios, r₁ and r₂, has been developed to describe the phenomena.Specifically, the Mayo-Lewis equation, also called the copolymerizationequation in polymer chemistry describes the distribution of monomers ina copolymer. Taking into consideration a monomer mix of two componentsM₁ and M₂ and the four different reactions that can take place at thereactive chain end terminating in either monomer (M*) with theirreaction rate constants k:

$\begin{matrix}{M_{1}^{*} + {{M_{1}\overset{k_{11}}{}M_{1}}M_{1}^{*}}} & (2) \\{M_{1}^{*} + {{M_{2}\overset{k_{12}}{}M_{1}}M_{2}^{*}}} & (3) \\{M_{2}^{*} + {{M_{1}\overset{k_{21}}{}M_{2}}M_{1}^{*}}} & (4) \\{M_{2}^{*} + {{M_{2}\overset{k_{22}}{}M_{2}}M_{2}^{*}}} & (5)\end{matrix}$

Reactivity ratios are defined as:

r ₁=(k ₁₁ /k ₁₂)  (6)

r ₂=(k ₂₂ /k ₂₁)  (7)

where k₁₁, k₁₂, k₂₁, and k₂₂ are the rate constants of the reactionsshown in equations 2 through 5, respectively.

A statistical random copolymer is generally formed when the values of r₁and r₂ are both equal to one. The reactivity ratio that corresponds toepsilon-caprolactone monomer adding to a chain terminated in a lactidylmoiety (i.e. polymerized L(−)-lactide sequence) has been experimentallydetermined to be 44 while L(−)-lactide monomer adding to a chainterminated in a caproyl moiety (i.e., polymerized epsilon-caprolactonesequence) has been determined to be 0.28. Since the two reactivityratios are quite different, this then leads to copolymers with aslightly non-random sequence distribution, even when both monomers areadded to the reactor together at the start of the polymerization.

For a given copolymer there are expected Harwood run numbers associatedwith each of the polymerized monomers, assuming the sequence is trulyrandom in nature. There is also an experimentally determined averagechain sequence length value for each of the components. Defined hereinis a “Randomness Factor” for each of the polymerized monomers; it isabbreviated as RF_(x), where x denotes the particular monomer underconsideration. The RF_(x) for monomer x is the ratio of theexperimentally determined average sequence length and the correspondingHarwood Run Number.

For instance, in the 20/80 AB random copolymer made up of A and B unitsdescribed previously, if it was indeed statically random, the expectedHarwood run numbers should be 1.25 and 5.0 for A and B, respectively. Ifexperimentally it was found that the average chain sequence lengthvalues for components A and B were 1.88 and 8.50 respectively, then onecould calculate an RF_(A) value of 1.5 (=1.88/1.25) and an RF_(B) valueof 1.7 (=8.5/5.0). Again the “randomness factor” is calculated from theratio of the experimentally determined average chain sequence length andthe corresponding theoretical Harwood Run Number assuming astatistically random sequence distribution.

An example of a random (copolyester) copolymer made from lactonemonomers is the copolymer made by combining of 70 moles of lactide and30 moles of epsilon-caprolactone into a reactor and polymerizing thecombination without introducing any additional monomer in a subsequentstep. It should be noted that a random (copolyester) copolymer made fromlactide and epsilon-caprolactone in the compositional range of 60/40 to75/25 will possess only very low levels of crystallinity, i.e., benearly amorphous. Such lactide/epsilon-caprolactone copolymerspossessing low levels of crystallinity will be unsuitable for use asstrong fibers due to a lack of dimensional stability in view of the highorientation needed to achieve high strength. It should also be notedthat random (copolyester) copolymers of even moderate molecular weight,made from lactide and epsilon-caprolactone in the compositional range of60/40 to 75/25, will possess glass transition temperatures greater thanroom temperature, leading to stiff articles.

An example of a non-random (copolyester) copolymer made from lactonemonomers or hydroxy acids is one in which the monomers are added to thereactor sequentially. For example, in a first stage of thepolymerization 70 moles of lactide and 30 moles of epsilon-caprolactoneare added to the reactor and polymerize this mixture; after thesubsequent formation of the “prepolymer”, an additional portion of oneof the monomers, or a third monomer, is added. The sequence distributionof monomers along the various chains is then purposefully controlled.

The copolymer useful in the practice of the present invention issemi-crystalline, while the prepolymer is amorphous. The prepolymercompositions being in the range of about 45/55 to about 30/70 and thefinal compositions about 60/40 to about 75/25, mole basis,L(−)-lactide/epsilon-caprolactone. It has been surprisingly andunexpectedly discovered that the copolymers useful in the practice ofthe present invention are semi-crystalline in nature with glasstransition temperatures well below room temperature. One possibleapplication for such polymers is in the production of novel, strong,soft, dimensionally stable foams, films, and nonwoven fabrics.

Poly(lactide) is a high glass transition (T_(g) of 60° C. to 65° C.),semi-crystalline polyester. This material has a high elastic modulus andis thus quite stiff making it generally unsuitable for monofilamentsurgical sutures, as pointed out in U.S. Patent Application 2013-0236499A1. The high (elastic) modulus exhibited by poly(lactide) also makes itunsuitable for foams that must be compressible with good recovery, aswell as unsuitable for soft, body-conforming films, or nonwoven fabrics;such articles, made from poly(lactide), are just too stiff. In addition,poly(lactide) foams, films and nonwovens do not absorb quickly enoughfor many key surgical applications, i.e., they last too long in vivo. Ithas been found, however, that certain copolymers of lactide andepsilon-caprolactone are, surprisingly and unexpectedly, particularlyuseful for applications requiring both softness and a longer termmechanical property loss profile.

For instance, a 72/28 mole/mole poly(lactide-co-epsilon-caprolactone)copolymer [72/28 Lac/Cap] was prepared in a sequential addition type ofpolymerization starting with a first stage charge of lactide andepsilon-caprolactone charge (45/55 Lac/Cap mole percent) followed by asubsequent second stage of lactide addition only. The total initialcharge was 75/25 mole/mole lactide/epsilon-caprolactone. Due toincomplete conversion of monomer-to-polymer and difference inreactivity, it is not uncommon to have the final (co)polymer compositiondiffer slightly from the feed composition. The final composition of thecopolymer was found to be 72/28 mole/mole lactide/epsilon-caprolactone.See Example 2A for the details of this copolymerization.

The present invention is directed toward medical devices in the form offoams, films and nonwoven fabrics made from copolymers of lactide andepsilon-caprolactone and methods of making such constructs. Morespecifically, this class of copolymers rich in lactide and made to havea blocky sequence distribution, that is non-random. In suchlactide/epsilon-caprolactone copolymers in which the majority of thematerial is based on lactide, the morphology of the polymer needs to beoptimized in order to be useful in long term applications. Appropriatepolymer morphology is particularly important in implantable medicaldevices. We have discovered that such compositions must be rich inlactide, e.g., having a polymerized lactide content of 50 percent orgreater.

Novel absorbable polymers have been, surprisingly and unexpectedly,discovered having a relatively narrow composition range and a non-randomsequence distribution, which when made into foams, films and nonwovenfabrics will yield foams, films and nonwoven fabrics that are softenough to have good handling characteristics, yet possess sufficientlyeffective mechanical integrity in vivo beyond 10 to 12 weeks postimplantation. Segmented, that is, possessing a non-random sequencedistribution beyond what would be expected based on reactivity ratioconsiderations, poly(lactide-co-epsilon-caprolactone) copolymerscomprising a polymerized lactide having a molar level between 60 to 75percent and a polymerized epsilon-caprolactone molar level between 25 to40 percent are useful in the practice of the present invention. Thisclass of copolymers, the poly(lactide-co-epsilon-caprolactone) familyrich in lactide, preferably contains about 25 to about 35 mole percentof polymerized epsilon-caprolactone.

Specifically, poly(lactide-co-epsilon-caprolactone) copolymers rich inpolymerized lactide having levels of incorporated lactide lower thanabout 60 mole percent are unsuitable for copolymers useful in thepractice of the present invention because of crystallizationdifficulties. On the other hand, poly(lactide-co-epsilon-caprolactone)copolymers rich in polymerized lactide having levels of incorporatedlactide greater than about 75 mole percent are unsuitable due to highmodulus and absorption times that are too long.

The dimensional stability of foams, films and nonwoven fabrics used tomanufacture surgical devices is very important to prevent shrinkage,both in the sterile package before use, as well as in the patient aftersurgical implantation. Dimensional stability in a low T_(g) material canbe achieved by crystallization of the formed article. Regarding thephenomena of crystallization of copolymers, a number of factors playimportant roles. These factors include overall chemical composition andsequence distribution. The dimensional stability of foams, films andnonwoven fabrics of the present invention is related to the ability ofthese articles to substantially maintain their physical dimensions evenwhen exposed to slightly elevated temperatures, for example 36° C.,and/or exposure to plasticizing gases such as ethylene oxide as mayoccur during sterilization. Although the overall level of crystallinity(and the T_(g) of the material) plays a role in dimensional stability,it is important to realize that the rate at which the crystallinity isachieved is critical to processing. If a lower T_(g) material isprocessed and its rate of crystallization is very slow, it is verydifficult to maintain dimensional tolerances since shrinkage and warpageeasily occur. Fast crystallization is thus an advantage. It has beendiscovered that for the systems at hand, in order to increase the rateof crystallization of a copolymer of given overall chemical composition,a block structure is preferable over a random sequence distribution.However, surprisingly and unexpectedly, it is now possible to achievethis with two lactone monomers, for instance lactide andepsilon-caprolactone, notwithstanding experimental difficulties andchallenges due to transesterification and other factors.

Useful in the practice of the present invention, the compositionalsequence of the inventive semi-crystalline copolymer is schematicallyillustrated as follows:

-   -   LLLLLLLLLLLLLL-CLCLCCLCLCLCCCLCLCCLC-LLLLLLLLLLLLLL    -   Polymerized Lactide Block-Polymerized        (Lactide-co-epsilon-Caprolactone)-Polymerized Lactide Block        with the semi-crystalline polylactide blocks representing        approximately 45 to 70 weight percent of the copolymer and with        the middle block formed from a nearly amorphous random        prepolymer based on polymerized lactide and        epsilon-caprolactone. In the above formula, L represents        lactide, and C represents epsilon-caprolactone.

The novel copolymers useful in the practice of the present invention areprepared by first polymerizing the lactide and epsilon-caprolactonemonomers at temperatures between about 170° C. and about 240° C.Temperatures between about 185° C. and about 195° C. are particularlyadvantageous. Although a monofunctional alcohol such as dodecanol mightbe used for initiation, a diol such as diethylene glycol has been foundto work well. Combinations of mono-functional and di-functional, ormultifunctional conventional initiators may also be used as a means offurther influencing some important characteristics such as morphologicaldevelopment including crystallization rates and ultimate crystallinitylevels. Reaction times can vary with catalyst level. Suitable catalystsinclude conventional catalysts such as stannous octoate. Sufficientlyeffective amounts of catalyst are utilized. The catalyst may be used atan overall monomer/catalyst level ranging from about 10,000/1 to about300,000/1, with a preferred level of about 25,000/1 to about 100,000/1.After the completion of this first stage of the polymerization (e.g., 4to 6 hours), the temperature is raised to above 200° C. (typically about205° C. to 210° C.). Once the temperature is increased, for example to205° C., the balance of lactide monomer can be added to the reactor;this can be conveniently done by pre-melting the monomer and adding itin a molten form. Once the second portion of lactide monomer is added,the temperature is brought to about 190° C. to about 200° C. to completethe co-polymerization (e.g., for about 1 to 2 hours).

It will be clear to one skilled in the art that various alternatepolymerization approaches and parameters are possible to produce thecopolymers of the present invention. For example, although notpreferred, it may be possible to conduct all or part of thepolymerizations without a catalyst present.

It is to be understood that the monomer feed added to the prepolymer maynot necessarily need to be pure lactide. Instead of adding pure lactidemonomer to the prepolymer, up to about ten mole percent of anothermonomer may be used to adjust the monomer feed added to the prepolymer.For instance, the monomer feed added to the prepolymer may contain minoramounts of epsilon-caprolactone; the monomer feed might be for instance90/10 lactide/epsilon-caprolactone. Adding epsilon-caprolactone to the“end blocks” will lower the melting point, crystallization rate andoverall crystallinity of the final copolymer. Adding more than about tenmole percent reduces properties too much to be useful for mostapplications. The compositional sequence of this variant of theinventive semi-crystalline copolymer is schematically illustrated asfollows:

-   -   LLCLLLLLLLLCLL-CLCLCCLCLCLCCCLCLCCLC-LLLLLLLCLLLLLL

In certain embodiments, it may be desirable to add minor amounts ofglycolide to the monomer feed added to the prepolymer. For instance, themonomer feed added to the prepolymer may contain up to about ten molepercent glycolide; the monomer feed might be for instance 90/10lactide/glycolide. Adding glycolide to the “end blocks” will lower themelting point, crystallization rate and overall crystallinity of thefinal copolymer, as well as increase the rate of absorption of thecopolymer. Again adding more than about ten mole percent reducesproperties too much to be useful for most applications. Thecompositional sequence of this variant of the inventive semi-crystallinecopolymer is schematically illustrated as follows:

-   -   LLLLLGLLLLLLLL-CLCLCCLCLCLCCCLCLCCLC-LLLLGLLLLLGLLL

In the above formula, L represents lactide, and C representsepsilon-caprolactone, and G represents glycolide.

It is also to be understood that slight modification of the first stageprepolymer monomer feed composition can be adjusted to provide certaindesired characteristics, all within the scope of the present invention.Thus other lactones such as p-dioxanone, trimethylene carbonate, orglycolide might be added to the lactide and epsilon-caprolactone mixtureof the first stage. The amount of another monomer that is added in thisfirst stage might be up to approximately, or about, 20 mole percent toadjust properties. For instance adding small amounts of glycolide to thelactide and epsilon-caprolactone in the first stage prepolymer monomerfeed will decrease the breaking strength retention profile of a suture;this may occur without affecting the crystallization rate or overallcrystallinity of the final copolymer. The compositional sequence of thisvariant of the inventive semi-crystalline copolymer is illustrated asfollows:

-   -   LLLLLLLLLLLLLL-CLGLCCLCLCLCGCLCLCCGC-LLLLLLLLLLLLLL

Polymerization variations include the possibility of adding the “secondstage” monomer to the prepolymer in multiple steps. Alternately,additional monomer may be added to the formed prepolymer in a continuousfashion over a short period of time, for instance 10 minutes or over arelatively longer period of time, for instance 2 hours.

Although adding all of the catalyst at the start of the polymerizationis described herein, that is, at the start of the formation of theprepolymer, alternatively only a portion of the catalyst may be added inthis stage of the polymerization, adding the remainder later, during theintroduction of the monomer to the now formed prepolymer.

It is to be understood that that sufficiently effective amounts ofacceptable coloring agents such as dyes and pigments might be added atany stage of the polymerization. Such colorants include D&C Violet No 2or D&C Green No 6.

The present invention can be practiced using the L(−) isomer of lactidemonomer, L(−)-lactide, or the D(+)isomer, D(+)-lactide. A mixture of thetwo monomers may be used, provided the resulting final copolymercrystallizes sufficiently to the extent needed to effectively providedimensional stability. One may then use a isomer lactide monomer blendcorresponding to 95 percent L(−)-lactide and 5 percent D(+)-lactide.Alternately, one may use a 50/50 mixture of the L and D isomers [aracemic mixture], in combination with an appropriate level ofepsilon-caprolactone to form the prepolymer, but use only L(−)-lactide[or D(+)-lactide] in the monomer feed to be introduced into the formedprepolymer. A copolymer so produced of the present invention will besemicrystalline in nature.

It is to be understood that low temperature polymerization techniquesmay also be used to make the copolymers of the present invention. As anexample, the reaction is maintained at the melt reaction temperature forsome period of time (e.g., about 3 to 4 hours), followed by thedischarge of the reaction product into suitable containers forsubsequent low temperature polymerization (e.g., 120° C.) for anextended period of time sufficient to effectively complete theco-polymerization. Higher monomer-to-polymer conversions may be possibleutilizing this alternate low temperature finishing approach.

Again, one skilled in the art can provide a variety of alternatepolymerization schemes to provide the novel copolymers of the presentinvention.

The novel copolymers useful in the practice of the present invention aresemicrystalline in nature, having a crystallinity level ranging fromabout 25 to about 50 percent. They will have a molecular weightsufficiently high to allow the medical devices formed therefrom toeffectively have the mechanical properties needed to perform theirintended function. For melt blown nonwoven structures and microsphereformation, the molecular weights may be a little lower, and forconventional melt extruded fibers, they may be a little higher.Typically, for example, the molecular weight of the copolymers of thepresent invention will be such so as to exhibit inherent viscosities asmeasured in hexafluoroisopropanol (HFIP, or hexafluoro-2-propanol) at25° C. and at a concentration of 0.1 g/dL between about 0.5 to about 2.5dL/g. More typical inherent viscosities of the copolymer may range fromabout 0.8 to about 2.0 dL/g with preferred values ranging from 1.2 toabout 1.8 dL/g, as measured in HFIP at 25° C. and at a concentration of0.1 g/dL.

In one embodiment, medical devices made of the copolymers useful in thepractice of the present invention may contain sufficiently effectiveamounts of conventional active ingredients or may have coatingscontaining such ingredients, such as antimicrobials, antibiotics,therapeutic agents, hemostatic agents, radio-opaque materials, tissuegrowth factors, and combinations thereof. In one embodiment theantimicrobial is Triclosan, PHMB, silver and silver derivatives, or anyother bio-active agent.

The variety of therapeutic agents that may be used is vast. In general,therapeutic agents which may be administered via these medical devicesand compositions of the present invention include, without limitation,antiinfectives, such as antibiotics and antiviral agents; analgesics andanalgesic combinations; anorexics; antihelmintics; antiarthritics;antiasthmatic agents; adhesion preventatives; anticonvulsants;antidepressants; antidiuretic agents; antidiarrheals; antihistamines;anti-inflammatory agents; antimigraine preparations; contraceptives;antinauseants; antineoplastics; antiparkinsonism drugs; antipruritics;antipsychotics; antipyretics, antispasmodics; anticholinergics;sympathomimetics; xanthine derivatives; cardiovascular preparationsincluding calcium channel blockers and beta-blockers such as pindololand antiarrhythmics; antihypertensives; diuretics; vasodilators,including general coronary, peripheral and cerebral; central nervoussystem stimulants; cough and cold preparations, including decongestants;hormones, such as estradiol and other steroids, includingcorticosteroids; hypnotics; immunosuppressives; muscle relaxants;parasympatholytics; psychostimulants; sedatives; tranquilizers;naturally derived or genetically engineered proteins, polysaccharides,glycoproteins, or lipoproteins; oligonucleotides, antibodies, antigens,cholinergics, chemotherapeutics, hemostatics, clot dissolving agents,radioactive agents and cystostatics. Therapeutically effective dosagesmay be determined by in vitro or in vivo methods. For each particularadditive or active ingredient, individual determinations may be made todetermine the optimal dosage required. The determination of effectivedosage levels to achieve the desired result will be within the realm ofone skilled in the art. The release rate of the additives or activeingredients may also be varied within the realm of one skilled in theart to determine an advantageous profile, depending on the therapeuticconditions to be treated.

The copolymers useful in the practice of the present invention can bemelt extruded by a variety of conventional means. Monofilament fiberformation can be accomplished by melt extrusion followed by extrudatedrawing with or without annealing. Multifilament fiber formation ispossible by conventional means. Methods of manufacturing monofilamentand multifilament braided sutures are disclosed in U.S. Pat. No.5,133,739, entitled “Segmented Copolymers of epsilon-Caprolactone andGlycolide” and U.S. Pat. No. 6,712,838 entitled “Braided Suture withImproved Knot Strength and Process to Produce Same”, which areincorporated by reference herein in their entirety.

The copolymers useful in the practice of the present invention may beused to manufacture conventional medical devices in addition to suturesusing conventional processes. For example, injection molding may beaccomplished after allowing the copolymer to crystallize in the mold;alternately, biocompatible nucleating agents might be added to thecopolymer to reduce cycle time. The copolymers of the present inventionmay be used to manufacture medical devices that function in part bybeing deformable without undergoing significant fracturing, cracking,splintering or other forms of breakage. Medical devices that function inpart by being deformable include those that have hinges or are requiredto bend substantially. The medical devices may include (but are notlimited to), conventional medical devices, especially implantablemedical devices, including staples, tacks, clips, sutures, barbedsutures, tissue fixation devices, mesh fixation devices, anastomosisdevices, suture and bone anchors, tissue and bone screws, bone plates,prostheses, support structures, tissue augmentation devices, tissueligating devices, patches, substrates, meshes, tissue engineeringscaffolds, drug delivery devices, and stents, etc.

The copolymers useful in the practice of the present invention may beused to produce inter-connected open cell porous foams bylyophilization. The lyophilization process is described as firstdissolving the copolymers in a suitable solvent to prepare a homogeneoussolution. Next, the polymer solution is subjected to a cooling thermaltreatment that freezes the solution in order to achieve phase separationbetween the polymer and solvent components and locks in the poremorphology. It should be appreciated by those skilled in the art, thatthe solvent crystals form the eventual pore structure of the foam. Thefrozen polymer-solvent system then undergoes a vacuum drying cycle thatremoves the solvent by sublimation leaving the porous polymer structure.The vacuum drying cycle is typically performed at multiple temperatures.“Primary drying” occurs by sublimation at a temperature below thefreezing point of the solvent; bulk solvent removal occurs during thisprocess. Often a “secondary drying” above the freezing point of thesolvent is used to remove any residual bound solvent by evaporation. Itis advantageous to remove the majority of solvent during primary drying.This is because at temperatures above the freezing point of the solventany significant amounts of remaining solvent could re-dissolve thepolymer and disrupt the porous structure of the foam. This is oftenreferred to as “melt-back” and can result in a product having a warpedor “potato chip”-like appearance.

The solvents used for lyophilization should be selected for suitabilityfor lyophilization (appropriate freezing temperatures, vapor pressure,etc.) and adequate polymer solubility. Solvents suitable forlyophilization include, but are not limited to, water, formic acid,ethyl formate, acetic acid, hexafluoroisopropanol (HFIP), cyclic ethers(i.e. TMF, DMF, and PDO), acetone, acetates of C2 to C5 alcohol (such asethyl acetate and t-butylacetate), glyme (i.e. monoglyme, ethyl glyme,diglyme, ethyl diglyme, triglyme, butyl diglyme, and tetraglyme),methyl-ethyl ketone, dipropyleneglycol methyl ether, lactones (such asγ-valerolatcone, δ-valerolactone, β-butyrolactone, γ-butyrolactone),1,4-dioxane, 1,3-dioxolane, 1,3-dioxolane-2-one (ethylene carbonate),dimethylcarbonate, benzene, toluene, benzyl alcohol, p-xylene,naphthalene, tetrahydrofuran, N-methyl pyrrolidone, dimethylformamide,chloroform, 1,2-dicholromethane, morpholine, dimethylsulfoxie,hexafluoroaceteone sesquihydrate (HFAS), anisole and mixtures thereof.Among these solvents, the preferred solvent of the present invention is1,4-dioxane.

The polymer solution is typically dispensed into a mold prior tolyophilization for two purposes: 1) to provide containment of the liquidpolymer solution for thermal treatment; and, 2) to provide a templatefor the shape of the resulting foam. The mold needs to have an openingto permit sublimation of the solvent. The mold can be made of anymaterial that is compatible with the solvent system in order to maintainmold integrity throughout the process. It is often preferred that themold is made of a material with a high thermal conductivity tofacilitate the heat transfer to the polymer solution for the thermaltreatment. The preferred mold materials for the present invention arealuminum and stainless steel.

Lyophilization for the present invention was carried out in aconventional tray-style freeze dryer (also known as a lyophilizationunit). The unit comprises a cabinet with several shelves that can beheated and cooled by a refrigeration system. These shelves enableheating and cooling for the thermal treatment and drying cyclestypically providing a shelf temperature range from −70° C. to 60° C.Polymer solutions can also be thermally treated in external coolingsystems including but not limited to refrigerators, liquid nitrogenbaths, and flash freezers. Thermal treatment can also include a stepwherein after initially freezing the polymer solution, the temperatureis raised above its Tg but below its freezing temperature to normalizethe solvent ice crystal size through Oswalt ripening. The interior ofthe cabinet of the lyophilization unit is connected directly to a vacuumpump that reduces the ambient gas pressure in the cabinet and acondenser that collects the solvent vapor that is sublimated from theproduct on a surface that is typically cooled to −40° C. to −80° C. Itshould be appreciated by those skilled in the art that lyophilizationcould be performed in other conventional freeze dryer configurationsincluding manifold and rotary freeze dryers.

The polymeric foams generated in this invention have interconnected andopen cell porous structures. Pore sizes can range from about 10 micronsto about 200 microns in diameter which typically result in the foamshaving an opaque white appearance. Foam density is directly associatedwith the concentration of the polymer solution and can typically rangefrom about 0.03 mg/cc to about 0.30 mg/cc.

The novel foams made from the copolymers useful in the practice of thepresent invention may be used in medical applications as scaffolds fortissue engineering, buttress materials, defect or space fillers, woundhealing dressing, 3D devices such as porous grafts, and otherimplantable wound healing, augmentation, and regeneration devices. Thefoams may have particular applications in bone or cartilagereengineering where the longer absorption times are preferred. The foamsmay be used in combination with other devices (such as meshes and othertextiles) or additives that can be added during the lyophilizationprocess. The foams may also be used as a drug delivery matrix whereby atherapeutic agent is mixed into the polymer solution before forming thefoam or loaded into the foam after it is formed.

The films made from the copolymers useful in the practice of the presentinvention may be used in medical applications as tissue separatingbarriers, reinforcing buttress materials, and adhesion prevention. Thefilms can be laminated with other devices (such as meshes and othertextiles) to form multilayer structures.

It is to be understood that the copolymers useful in the practice of thepresent invention may be used to make fabrics via conventional meltblown nonwoven techniques. In addition, due to the expected goodsolubility in common organic solvents of the copolymers of the presentinvention, useful medical devices can be made by electrostatic spinningtechniques. Similarly, the copolymers of the present invention may alsobe used to manufacture microcapsules and microspheres; these may be madeto contain therapeutic agents for delivery to the patient.

It was found that the foam parts made from the copolymers useful in thepractice of the present invention exhibited excellent dimensionalstability during manufacture, during ethylene oxide sterilization, andupon storage of packaged products, especially compared to the randomcopolymers described in Vyakarnam, et al.

Surprisingly, despite possessing nonrandom molecular architecture, andhigh levels of crystallinity, it was found that the copolymers ofAndjelic and Jamiolkowski in U.S. Patent Application 2013/0236499 A1(incorporated by reference) unexpectedly do not exhibit gel formationovercoming some challenges in the lyophilization manufacturing processespresented by other copolymers, for example, the copolymers of Donners,et al.

Surprisingly, it was also found that substantially higher loading levelsin at least one preferred solvent, 1,4-dioxane, can be achieved with thecopolymers used in the foams, films, and methods of the presentinvention compared to their counterparts described in Vyakarnam, et al.and Donners, et al. Higher loading levels are valuable because theresultant foams will generally have higher mechanical propertiescompared with foams of lower bulk density.

Additionally, it was found that at a given bulk density, the copolymersuseful in the practice of the present invention and the copolymers ofDonners, et al. provide higher mechanical properties at a given foambulk density due to the higher crystallinity that are achievable withthese resins as compared to the copolymers described in Vyakarnam et al.

Most importantly, however, it was found that the inventive foams of thepresent application degrade at a much slower rate than those ofVyakarnam, et al. and Donners, et al. The extended mechanical propertyloss profiles exhibited post-implantation are very important in certainkey surgical procedures. To be clear, the Vyakarnam, et al. foamsexhibit zero residual strength under compression at approximately 25days of in vitro treatment at 37° C. and pH 7.27 and the Donners et al.foams exhibit zero residual strength at approximately 40 days under thesame in vitro testing conditions. Advantageously, the foams of thepresent invention last longer than 64 days.

In summary, the novel foams, films and processes of the presentinvention exhibit the following advantages over the prior art: lack gelformation leading to robust manufacturing processes while simultaneouslyproviding moderate to high crystallinity levels in the foam; provide thepossibility of higher loading levels; display higher mechanicalproperties due both to the higher crystallinity that are achievable at agiven foam bulk density [based on the solids content of the solution tobe lyophilized], as well to the higher bulk densities achievable due tothe higher solution loading possible; good dimensional stability of thefoam parts during manufacture, ethylene oxide sterilization, andstorage; and finally, extended mechanical property loss profilesexhibited post-implantation.

The following examples are illustrative of the principles and practiceof the present invention, although not limited thereto.

Example 1 Synthesis of Segmented Block CopolymerPoly(L(−)-lactide-co-epsilon-caprolactone) at 64/36 by Mole [InitialFeed Charge of 70/30 Lac/Cap]

Using a conventional 2-gallon stainless steel oil jacketed reactorequipped with agitation, 1,520 grams of epsilon-caprolactone and 1,571grams of L(−)-lactide were added along with 3.37 grams of diethyleneglycol and 2.34 mL of a 0.33M solution of stannous octoate in toluene.After the initial charge, a purging cycle with agitation at a rotationalspeed of 10 RPM in a downward direction was initiated. The reactor wasevacuated to pressures less than 150 mTorr followed by the introductionof nitrogen gas. The cycle was repeated once again to ensure a dryatmosphere. At the end of the final nitrogen purge, the pressure wasadjusted to be slightly above one atmosphere. The rotational speed ofthe agitator was reduced to 7 RPM in a downward direction. The vesselwas heated by setting the oil controller at 190° C. When the batchtemperature reached 110° C., rotation of the agitator was switched to anupward direction. The reaction continued for 4.5 hours from the time theoil temperature reached 190° C.

After the completion of the first stage portion of the polymerization, avery small amount of resin was discharged for analysis purposes;selected characterization was performed. The chemical composition of theprepolymer, as determined by NMR, was 45 mole percent polymerizedlactide and 55 mole percent polymerized caprolactone with about 2percent of residual unreacted monomer. The DSC data revealed that theprepolymer was fully amorphous with no crystallinity developed evenafter heat treatment. The glass transition temperature was determined tobe −17° C. (minus 17° C.).

In the second stage portion of the polymerization, the heating oilcontroller set point was raised to 205° C., and 2,909 grams of moltenL(−)-lactide monomer was added from a melt tank with the agitator speedof 12.5 RPM in a downward direction for 15 minutes. The agitator speedwas then reduced to 7.5 RPM in the downward direction. The oilcontroller was then decreased to 200° C. and the reaction proceeded anadditional 2.5 hours prior to the discharge.

At the end of the final reaction period, the agitator speed was reducedto 2 RPM in the downward direction, and the polymer was discharged fromthe vessel into suitable containers. Upon cooling, the polymer wasremoved from the containers and placed into a freezer set atapproximately −20° C. for a minimum of 24 hours. The polymer was thenremoved from the freezer and placed into a Cumberland granulator fittedwith a sizing screen to reduce the polymer granules to approximately3/16 inches in size. The granules were sieved to remove any “fines” andweighed. The net weight of the ground and sieved polymer was 5.065 kg;the ground polymer was then placed into a 3 cubic foot Patterson-Kelleytumble dryer to remove any residual monomer.

The Patterson-Kelley tumble dryer was closed, and the pressure wasreduced to less than 200 mTorr. Once the pressure was below 200 mTorr,the dryer rotation was activated at a rotational speed of 10 RPM with noheat for 18 hours. After the 18 hour period, the oil jacket temperaturewas set to 55° C. with drying at this temperature for 4 hours. The oiltemperature was again raised, this time to 65° C.; this period lasted 2hours. Two additional heating periods were employed: 85° C. for 12hours, and 110° C. for 3 hours. At the end of the final heating period,the batch was allowed to cool for a period of 4 hours while maintainingrotation and vacuum. The polymer was discharged from the dryer bypressurizing the vessel with nitrogen, opening the discharge valve, andallowing the polymer granules to descend into waiting vessels for longterm storage.

The long term storage vessels were air tight and outfitted with valvesallowing for evacuation so that the resin was stored under vacuum. Thedried resin exhibited an inherent viscosity of 1.27 dL/g, as measured inhexafluoroisopropanol at 25° C. and at a concentration of 0.10 g/dL. Gelpermeation chromatography analysis showed a weight average molecularweight of approximately 60,000 Daltons. Nuclear magnetic resonanceanalysis confirmed that the resin contained 64 mole percent polymerizedL(−)-lactide and 36 mole percent polymerized epsilon-caprolactone, witha residual monomer content of about 1.6 percent. The glass transitiontemperature, T_(g), of the dried resin was −17° C., the melting pointwas 160° C., and the heat of fusion, ΔH_(m), was 26 J/g as determined byDifferential Scanning calorimetry using the first heat scan and aheating rate of 10° C./min. Wide Angle X-ray Diffraction (WAXD) analysisrevealed that the dried resin contains 34 percent of crystallinity.

Example 2A Synthesis of Segmented Block CopolymerPoly(L(−)-lactide-co-epsilon-caprolactone) at 72/28 by Mole [InitialFeed Charge of 75/25 Lac/Cap]

Using a conventional 10-gallon stainless steel oil-jacketed reactorequipped with agitation, 5,221 grams of epsilon-caprolactone and 5,394grams of L(−)-lactide were added along with 13.36 grams of diethyleneglycol and 9.64 mL of a 0.33M solution of stannous octoate in toluene.After the initial charge, a purging cycle with agitation at a rotationalspeed of 10 RPM in a downward direction was initiated. The reactor wasevacuated to pressures less than 150 mTorr followed by the introductionof nitrogen gas. The cycle was repeated once again to ensure a dryatmosphere. At the end of the final nitrogen purge, the pressure wasadjusted to be slightly above one atmosphere. The rotational speed ofthe agitator was reduced to 7 RPM in a downward direction. The vesselwas heated by setting the oil controller at 190° C. When the batchtemperature reached 110° C., rotation of the agitator was switched tothe upward direction. The reaction continued for 6 hours from the timethe oil temperature reached 190° C.

After the completion of the first stage portion of the polymerization, avery small amount of resin was discharged for analytical purposes;selected characterization was performed. The chemical composition of theprepolymer was the same as in Example 1: 45/55 Lac/Cap mole percent withabout 2 percent of residual monomer as determined by NMR. The DSC datarevealed that the prepolymer was fully amorphous with no crystallinitydeveloped, even after heat treatment. The glass transition temperaturewas again determined to be −17° C. (minus 17° C.).

In the second stage, the oil controller set point was raised to 205° C.,and 14,384 grams of molten L(−)-lactide monomer was added from a melttank with an agitator speed of 12.5 RPM in a downward direction for 15minutes. The agitator speed was then reduced to 7.5 RPM in the downwarddirection. The oil controller was then decreased to 190° C. and thereaction proceeded an additional 3 hours prior to the discharge. At theend of the final reaction period, the agitator speed was reduced to 2RPM in the downward direction, and the polymer was discharged from thevessel into suitable containers.

The resin was divided into two portions. A minor portion of the dividedresin was treated as described in Example 2B. The major portion of thecopolymer, 13,930 grams, was subjected to the same grinding, sieving anddrying steps described in Example 1 using the following heat/dryingtreatment: 12 hours at 25° C., 4 hours at 55° C., 4 hours at 75° C., and12 hours at 110° C., respectively.

The dried resin exhibited an inherent viscosity of 1.52 dL/g, asmeasured in hexafluoroisopropanol at 25° C. and at a concentration of0.10 g/dL. Gel permeation chromatography analysis showed a weightaverage molecular weight of approximately 79,000 Daltons. Nuclearmagnetic resonance analysis confirmed that the resin contained 72 molepercent polymerized L(−)-lactide and 28 mole percent polymerizedepsilon-caprolactone with a residual monomer content of about 1.5percent. The glass transition temperature, T_(g), of the dried resin was−8° C., the melting point was 169° C., and the heat of fusion, ΔH_(m),was 33 J/g as determined by Differential Scanning calorimetry using thefirst heat scan procedure and the heating rate of 10° C./min. Wide AngleX-ray Diffraction (WAXD) analysis revealed that the dried resincontained 43 percent crystallinity.

Example 2B Synthesis of Segmented Block CopolymerPoly(L(−)-lactide-co-epsilon-caprolactone) at 74/26 by Mole [InitialFeed Charge of 75/25 Lac/Cap, solid-state polymerization finaltreatment]

The smaller portion of the discharged resin, 6,900 grams, produced anddescribed in Example 2A above was placed in a nitrogen purged oven andheated for 72 hours at 120° C. This solid state polymerization step wasconducted in order to further increase the monomer conversion. After thesolid state polymerization treatment, the resin was ground, sieved, anddried using the same procedures described earlier in Examples 1 and 2A.

The dried resin exhibited an inherent viscosity of 1.58 dL/g, asmeasured in hexafluoroisopropanol at 25° C. and at a concentration of0.10 g/dL. Gel permeation chromatography analysis showed a weightaverage molecular weight of approximately 83,000 Daltons. Nuclearmagnetic resonance analysis confirmed that the resin contained 74 molepercent polymerized L(−)-lactide and 26 mole percent polymerizedepsilon-caprolactone with a residual monomer content of about 1.0percent. The glass transition temperature, T_(g), of the dried resin was−8° C., the melting point was 168° C., and the heat of fusion, ΔH_(m),was 39 J/g as determined by Differential Scanning calorimetry usingfirst heat data and a heating rate of 10° C./min. Wide Angle X-rayDiffraction (WAXD) analysis revealed that the dried resin was 43 percentcrystalline.

Example 3A Synthesis of Segmented Block CopolymerPoly(L(−)-lactide-co-epsilon-caprolactone) at 74/26 by Mole [InitialFeed Charge of 75/25 Lac/Cap]

Using a conventional 10-gallon stainless steel oil jacketed reactorequipped with agitation, 5,221 grams of epsilon-caprolactone and 2,826grams of L(−)-lactide were added along with 9.65 grams of diethyleneglycol and 9.64 mL of a 0.33M solution of stannous octoate in toluene.The reactor's conditions were identical those in Example 2A, except thatthe reaction in the first stage lasted for 4 hours from the time the oiltemperature reached 190° C.

After the completion of the first polymerization stage, a very smallamount of resin was discharged for analysis purposes; selectedcharacterization was performed. The chemical composition of theprepolymer in this case was 30/70 Lac/Cap mole percent with about 3percent of residual monomer as determined by NMR. The DSC data revealedthat the prepolymer was fully amorphous with no crystallinity developedeven after heat treatment. The glass transition temperature was found tobe lower than that in Examples 1 and 2A, −39° C. (minus 39° C.), mostlikely due to the higher epsilon-caprolactone content present in thefirst stage.

In the second stage, the oil controller set point was raised to 205° C.,and 16,953 grams of molten L(−)-lactide monomer was added from a melttank. The oil controller was then decreased to 200° C. and the reactioncontinued an additional 3 hours prior to the discharge.

The major portion of the copolymer, 13,870 grams, was subjected to thesame grinding, sieving and drying steps described in Example 1 using thefollowing heat/drying treatment: 12 hours at 25° C., 4 hours at 55° C.,4 hours at 75° C., and 12 hours at 110° C. (the same conditions as forExample 2A).

The dried resin exhibited an inherent viscosity of 1.63 dL/g, asmeasured in hexafluoroisopropanol at 25° C. and at a concentration of0.10 g/dL. Gel permeation chromatography analysis showed a weightaverage molecular weight of approximately 90,000 Daltons. Nuclearmagnetic resonance analysis confirmed that the resin contained 74 molepercent polymerized L(−)-lactide and 26 mole percent polymerizedepsilon-caprolactone with a residual monomer content of about 1.5percent. The glass transition temperature, T_(g), of the dried resin was−34° C., the melting point was 170° C., and the heat of fusion, ΔH_(m),was 35 J/g, as determined by Differential Scanning calorimetry using thefirst heat data and a heating rate of 10° C./min. Wide Angle X-rayDiffraction (WAXD) analysis revealed that the dried resin was 45 percentcrystalline.

Example 3B Synthesis of Segmented Block CopolymerPoly(L(−)-lactide-co-epsilon-caprolactone) at 76/24 by Mole [InitialFeed Charge of 75/25 Lac/Cap, Solid-state Polymerization FinalTreatment]

The smaller portion of the discharged resin, 8,500 grams, produced anddescribed in Example 3A, was placed in a nitrogen purged oven and heatedin a solid state fashion for 72 hours at 120° C. This step was conductedin order to further increase the monomer conversion. After the solidstate polymerization treatment, the resin was ground, sieved, and driedusing the same procedures described earlier in earlier examples.

The dried resin exhibited an inherent viscosity of 1.70 dL/g, asmeasured in hexafluoroisopropanol at 25° C. and at a concentration of0.10 g/dL. Gel permeation chromatography analysis showed a weightaverage molecular weight of approximately 91,000 Daltons. Nuclearmagnetic resonance analysis confirmed that the resin contained 76 molepercent polymerized L(−)-lactide and 24 mole percent polymerizedepsilon-caprolactone with a residual monomer content of about 1.0percent. The glass transition temperature, T_(g), of the dried resin was−34° C., the melting point was 170° C., and the heat of fusion, ΔH_(m),was 49 J/g, as determined by Differential Scanning calorimetry using thefirst heat data and a heating rate of 10° C./min. Wide Angle X-rayDiffraction (WAXD) analysis revealed that the dried resin was 50 percentcrystalline.

Example 4 Selected Properties of Copolymers of the Present Invention

a) Differential Scanning Calorimetry (DSC) and Melt Index (MI)Characteristics

DSC measurements were conducted using a model Q20-3290 calorimeter fromTA Instruments (New Castle, Del.) equipped with automatic sampler. Inindividual experiments, the dried, heat treated copolymer resins asdescribed in Examples 1, 2A, 2B, 3A, and 3B were placed into DSC pans,quenched below −60° C., and heated at the constant heating rate of 10°C./min to determine their calorimetric properties (first heatproperties); these included the glass transition temperature, T_(g), themelting point, T_(m) and the heat of fusion, ΔH_(m). From the secondheat measurements (resin was melted at 200° C. and then quenched below−60° C.), values for T_(g), T_(m), T_(c) (crystallization temperature),and ΔH_(m) were obtained that are independent from the previous heattreatment history. Data obtained using calorimetry and melt indexmeasurements are displayed in Table 1.

TABLE 1 Melt Index, MI and DSC Results during the First and Second HeatRuns on the Copolymers of the Present Invention First heat, DSC Secondheat, DSC MI T_(g) T_(m) ΔH_(m) T_(g) T_(c)/T_(m) ΔH_(m) Example (g/10min) (° C.) (° C.) (J/g) (° C.) (° C.) (J/g) 1  0.224 −17 160 26 12106/160 21 2A 0.066 −8 169 33 29 125/168 25 2B 0.052 −8 168 39 33128/168 24 3A 0.016 −34 170 35 −32 & 53 124/169 28 3B 0.018 −34 170 49−35 & 53 125/168 29

The results in Table 1 indicated that the resin of Example 1 exhibited alower overall crystallinity level (lower ΔH_(m) value), and a lowermelting point than the rest of the examples. This is most likely due toa higher polymerized epsilon-caprolactone content present in thiscopolymer (36 mole percent) compared to the other resins. As notedbefore, the resin of Example 1 also has lower weight average molecularweight and IV. With an increase in polymerized lactide level in thestructure (Examples 2A-B, 3A-B), the level of crystallinity increases(higher ΔH_(m) values), as well as the melting point values. It is veryimportant to note that in all cases only a single T_(g) was observedafter the first heating scans. The T_(g) values were all well below roomtemperature, ranging from minus 8° to minus 34° C.; low T_(g) values maycontribute to increased softness of medical devices produced from thesematerials.

Melt Index (MI) is used as a measure of the melt viscosity of theresins. MI experiments on dried resins of present invention wereconducted using an Extrusion Plastometer, Tinius Olsen (Willow Grove,Pa., USA) at 175° C. with the nominal weight of 2,060 g. The die used inthe MI measurements had a capillary with a diameter of approximately0.023 inches and a length 0.315 inches. The MI data (second column inTable 1) indicate the lowest melt viscosity for Example 1, and thehighest for Examples 3A and 3B, which is in agreement with the molecularweight and IV data mentioned earlier.

In order to gain preliminary information on potential fibercharacteristics, the copolymers of the present invention were extrudedthrough the Melt Index apparatus (at 215° C.), unoriented fiber partscollected, and then subjected to manual heat or cold drawing processuntil the fibers were fully stretched. Pieces of drawn fibers wereexamined for handling purposes only. It was found that fibers from allresins from the present invention (Examples 1 to 3B) showed goodpliability and softness suitable for making monofilaments.

b) Isothermal Crystallization Kinetics by DSC

Crystallization characteristics were assessed. Isothermalcrystallization kinetics of the polymers of the present invention wereconducted using the Differential Scanning calorimetry techniques. Thedried, heat-treated copolymer resins, as described in Examples 1, 2A,2B, 3A, and 3B were placed into a DSC pan and completely melted at 200°C. for 2 minutes to remove any nucleation sites present in the sample.Subsequently, tested materials were rapidly cooled/quenched (rate −65°C./min) to the desired crystallization temperatures. The isothermalmethod assumes that no crystallization occurs before the sample reachesthe test temperature; the data obtained supported this assumption.Crystallization behavior of the five samples was characterized over awide range of temperatures, between 40° C. and 130° C. Isothermalcrystallization kinetics (at constant temperature) were monitored as achange in heat flow as a function of time. The isothermal heat flowcurve was integrated to determine the crystallinity parameters. It isworth noting that the isothermal DSC runs were made in randomized orderto avoid any bias.

The development of crystallinity with time can be accessed from thedegree of crystallization, α, which is expressed by the ratio

$\begin{matrix}{\alpha = {\frac{\Delta \; {Ht}}{\Delta \; H\; \infty} = \frac{\int_{0}^{t}{\frac{dQ}{dt}{dt}}}{\int_{0}^{\infty}{\frac{dQ}{dt}{dt}}}}} & (8)\end{matrix}$

where dQ/dt is the respective heat flow; dH_(t), the partial areabetween the DSC curve and the time axis at time t; and dH_(∞), the totalarea under the peak and corresponds to the overall heat ofcrystallization. The degree of crystallization, α, is then thecrystalline volume fraction developed at time t.

After performing the integration of the heat flow/time curve, thecrystallization half-time, t_(1/2), can be determined. Thecrystallization half-time is the time needed to reach 50 percentcrystallinity of the total amount developed during the isothermal run.In order to express crystallization kinetics, a reciprocalcrystallization half-time was presented as a function of crystallizationtemperature. These data are shown in FIG. 1 for resins of Examples 1 and3A. The resins 2A, 2B, and 3B were also examined; both 2A and 2B samplesshow very similar trend as Example 1. The resins 3A, 3B behaved nearlyidentically to each other. Several important points can be drawn fromthe data in FIG. 1. Firstly, all examined resins showed a fastcrystallization rate over a wide range of temperatures, especially whencompared to random copolymers of the same composition. Fastest kineticsfor the examined resins were observed at approximately 95° C.

Interestingly, the plot of Example 1 (FIG. 1) showed an unusual, secondmaximum at lower crystallization temperature (around 65° C.); the resinsof Examples 2A and 2B displayed a second maximum at the same temperatureas well. This information may be very useful, for instance, foroptimizing extrusion conditions to increase crystallization efficiencyduring the drawing process. On the other hand, the samples 3A and 3B didnot exhibit this lower temperature maximum; here, only a regularbell-shaped curve was observed with the crystallization rates similar tothose of Example 1. The lack of a low temperature maximum in FIG. 1 for3A and 3B resins may possibly be due to higher second heat T_(g) valuesfor these copolymers as previously reported in Table 1.

Example 5 Hydrolysis Profile Data—Comparison with Poly(p-dioxanone)

The absorbability of the resins of the subject invention was assessed byan in vitro method. The method was found suitable for estimatingsynthetic absorbable polyester in vivo degradation time. Essentially,the article to be tested is subjected to hydrolysis at a given testtemperature and a constant pH. Using pH-stat technology, a solution ofweak base is added to the test article in an aqueous environment and theamount of base added as a function of time is recorded. In vivoabsorption time is compared to the generated in vitro data, initiallywith model compounds and a number of commercially available absorbableproducts to establish a correlation curve.

In vitro absorption time was measured by an automated titration unit(718 Stat Titrino, Brinkmann, Westbury, N.Y., USA) at 70° C., underconstant pH (7.3) in 70 mL of deionized (DI) water using 0.05N NaOH as abase. The weight of materials was about 100 mg. All of the polymersamples were in granular form with 6 pieces chosen for each resin havingsimilar shape and size.

Hydrolysis data indicated that all examined materials hydrolyzed underthe test conditions with the rate of disappearance of the copolymers ofthe present invention being slower than the control sample,poly(p-dioxanone) homopolymer. Hydrolysis results are presented in Table2 in a form of hydrolysis half-time. Hydrolysis half-time is defined astime needed to hydrolyze half of the ester groups originally present.Shorter times suggest faster hydrolysis and vice versa.

TABLE 2 Hydrolysis Profile Data of Poly(p-dioxanone), PDS Dried Resinand the Final, Heat Treated Copolymers of the Present Invention ResinShape & Hydrolysis Size (# of % C Did half- Ex- Composition pieces andby Hydrolysis time, ample (mole %) total weight) WAXD Occur? t_(1/2)(hours) 1 64/36 Granular, 34 Yes 300 Lac/Cap 6 pieces, 96 mg 2A 72/28Granular, 43 Yes 240 Lac/Cap 6 pieces, 96 mg 3A 74/26 Granular, 45 Yes260 Lac/Cap 6 pieces, 97 mg PDS 100% PDO Granular, 55 Yes 100 6 pieces,97 mg

It is evident from Table 2 that the inventive copolymers of Examples (1,2A, and 3A) all exhibited a slower hydrolysis rate than thepoly(p-dioxanone) homopolymer control, despite the fact that theyexhibited lower levels of crystallinity.

Example 6 Determination of the Average Chain Sequence Length (ACSL) ofthe Segmented Poly(L(−)-lactide-co-epsilon-caprolactone) Segmented BlockCopolymers

The copolymers described in the Examples 1, 2A, 2B, 3A and 3B weresubjected to ¹³C NMR analysis (UNITYplus, Varian 400 MHz NMR system) toexperimentally determine an average chain sequence length, ACSL forcaproyl and lactidyl blocks (ACSL_(cap) and ACSL_(LL), respectively).The peak assignments and method analysis used were based on the workreported earlier on a similar class of copolymers (Z. Wei et al./Polymer50 (2009) 1423-1429). Listed in Table 3 are the final compositions(polymerized lactide/epsilon-caprolactone mole ratio), the ACSL_(LL) andACSL_(cap) values, the random factors for polymerized lactide andepsilon-caprolactone, RF_(LL) and RF_(cap), respectively for the finalcopolymers of Examples 1, 2A, 2B, 3A and 3B as well as some comparativeprior art copolymers. Comparative Copolymer X is a melt prepared randomcopolymer reported by Wei et al. in 2009 (Z. Wei et al./Polymer 50(2009) 1423-1429); Comparative Copolymer Y is a solution prepared randomcopolymer reported by Vanhoorne, et al. in 1992 (Vanhoorne, etal./Macromolecules 25 (1992) 37-44; and Comparative Copolymer Z is amelt prepared block copolymer reported by Baimark, et al. in 2005(Journal of Materials Science: Materials In Medicine 16 (2005) 699-707).

TABLE 3 ¹³C NMR Data on the Polymers of the Present Invention FinalComposition Lac/ε-Cap Example (mole %) ACSL_(LL) ACSL_(Cap) RF_(LL)RF_(Cap) 1 64/36 6.7 3.3 2.41 2.11 (34% cryst.) 2A 72/28 7.3 2.3 2.041.66 (43% cryst.) 2B 74/26 7.4 2.2 1.92 1.63 (43% cryst.) 3A 74/26 11.13.1 2.89 2.29 (45% cryst.) 3B 76/24 10.8 3.3 2.59 2.51 (50% cryst.)Comparative 64/36 4.6 2.4 1.66 1.54 Copolymer X (random) Comparative70/30 5.1 2.2 1.53 1.54 Copolymer Y (random) Comparative 79/21 8.2 2.31.72 1.82 Copolymer Z (block)

Data in Table 3 indicate that for inventive Examples 1, 2A, 2B, 3A, and3B, the average chain sequence lengths, ACSL, for caproyl and lactidylblocks (ACSL_(cap) and ACSL_(LL), respectively), are relatively long vs.the comparative polymers of similar compositions. Shown in FIG. 2 arethe relative proportions, on a mole basis, of a variety of 3-member,4-member, and 5-member sequence combinations; specifically, CCC, LLCC,CCLL, LLCLL, LLLLC, CLLC, CLLLL, and LLLLL. A particularly importantsequence combination is the 5-member LLLLL, as it reflects the relativeamount of crystallizable lactide in the copolymer, resulting inincreased crystallizability and consequently dimensional stability ofarticles formed therefrom.

The randomness factors for the lactidyl blocks (RF_(LL)) of theinventive Examples, as shown in Table 3, are particularly large values.Having high randomness factor parameters indicates much higherblockiness of the lactide sequences in the inventive samples than thecomparative examples. A consequence of possessing a high level ofblockiness in the copolymers of the current invention is enhancedcrystallization rates and ultimate crystallinity levels will beenhanced, leading to better fiber properties.

Example 7 Foam Formation by Lyophilization of the Resin of Example 1

a) Solution Preparation

Solutions were prepared by weighing out 20 grams of the polymer ofExample 1 and 180 grams of anhydrous 1,4-dioxane to achieve a 10% (w/w)solution concentration. The two components were combined in anErlenmeyer flask, which was then fitted with a stir bar and placed in awater bath. The solution was heated at 70° C. with agitation for 1 to 2hours. After removal from heat, the solution was then filtered throughan extra course filter under gentle nitrogen pressure.

A sample of solution was then taken to measure the concentration via dryweight measurement. After recording the weight of the solution, the1,4-dioxane was removed by allowing it to evaporate overnight and thensubsequently dried in a vacuum oven heated to 50° C. for 48 hrs. Theconcentration of the solution was measured to be 10.1% (w/w).

b) Lyophilization

Lyophilization of the polymer solution into a foam construct was carriedout in a LyoStar3 unit manufactured by SP Scientific.

Prior to lyophilization, the solution was heated to 75° C. forapproximately 1 hour. The hot polymer solution was dispensed into astainless steel mold having 30 cavities; each cavity had a configurationof a strip that was approximately 10 mm×60 mm×3 mm. Once filled, themold was immediately placed into the lyophilization unit chamber thatwas preset to a temperature of −45° C. The lyophilization cycle was theninitiated as specified by a computer controlled process steps (recipe).The recipe was comprised of the following sequences:

-   -   1. Thermal Treatment: The chamber was held at −45° C. for 1 hr        and then ramped to 3° C. at a rate of 1° C./min. The unit was        then held at 3° C. for 1 hr and then ramped back to −45° C. at a        rate of −0.5° C./min for a hold of 1 hr.    -   2. Evacuation then commenced by pulling vacuum to 450 mTorr.        Once that level was achieved, the unit was held at −45° C. for 2        hrs.    -   3. Drying was then started by ramping the unit to −10° C. at a        rate of 0.5° C./min and held for 9 hrs. The vacuum level was        then decreased to 20 mTorr and the shelf temperature was        increased to 10° C. at a rate of 0.25° C./min and held for 2        hrs. The shelf temperature was then increased to 20° C. at a        rate of 2° C./min and kept at that level until the cycle was        stopped and vacuum was broken with nitrogen.

Following lyophilization, the foam strips were removed from the moldsand stored under nitrogen until further use.

b) Annealing

Annealing was conducted under nitrogen using a Thermal Product SolutionsBlue M Oven (Model No: DCI-296-G-G-MP750). Foams were placed on theshelf of the oven without any fixation. After purging the unit withnitrogen for 1 hour, the temperature of the oven was ramped to 90° C.and held there for 6 hours before returning to room temperature. Afterannealing, the foam strips were stored under nitrogen until further use.

Example 8 Foam Formation by Lyophilization of the Resin of Example 2A

a) Solution Preparation

Two separate solutions were prepared with 10% and 20% (w/w)concentrations. For the 10% solution, 20 grams of the polymer of Example2A and 180 grams of anhydrous 1,4-dioxane were weighed out. For the 20%solution, 40 grams of the same polymer and 160 grams of anhydrous1,4-dioxane were weighed out. The components for each solution werecombined in separate Erlenmeyer flasks, which were then fitted with astir bar and placed in separate water baths. Solutions were heated at80° C. with agitation for 1 to 2 hours. After removal from heat, thesolutions were then filtered through an extra course filter under gentlenitrogen pressure.

A sample of solution was then taken to measure the concentration via dryweight measurement. After recording the weight of the solution, the1,4-dioxane was removed by allowing it to evaporate overnight and thensubsequently dried in a vacuum over heated to 50° C. for 48 hrs. Theconcentrations of the 10% and 20% solutions were measured to be 10.2%and 21.4% (w/w), respectively.

b) Lyophilization

Lyophilization of the polymer solutions into a foam construct wascarried out as described in Example 7 above.

c) Annealing

Annealing of the foams was carried out as described in Example 7 above.

Example 9 Foam Formation by Lyophilization of the Resin of Example 3A

Foams were prepared with the polymer of Example 3A using identicalsolution preparation, lyophilization, and annealing as described inExample 8 above. The measured concentration of the solution was 10.3%(w/w).

Example 10 Subjective Mechanical Property Description of Foam

The four foams produced in Examples 7, 8, and 9 were white in appearanceand smooth to the touch. All maintained their integrity after repeatedmanual bending and compression procedures. The foam made in Example 7exhibited very good recovery to its original form after compression. Thefoams made with the 10% and 20% solution in Example 8 showed differentphysical properties. The 20% solution foam was nearly incompressible andcould be described as “brick-like”. The foam made with the 10% solutionwas compressible but did not exhibit complete recovery to shape aftersqueezing it like the foam in Example 7. The foam made in Example 9 hadsimilar properties to the 10% solution foam from Example 8.

Example 11 In Vitro Test Methods Determination of Polymer Solubility in1,4-dioxane

The maximum solubility of a variety of absorbable polymers in1,4-dioxane was evaluated by adding a given polymer resin in 1 gincrements to 100 ml of 1,4-dioxane in a 250 ml roundbottom flask fittedwith a nitrogen inlet adapter to maintain an inert atmosphere. Thesolution was heated to 85° C. and if the resin dissolved in less than 2hrs another addition of 1 g polymer resin was made until either thesolution formed a gel at elevated temperature or particulates remainedafter 2 hours of heating.

Determination of the Onset of Gelation

When gel formation occurs there is a distinct change in the viscosity ofthe solution. The onset of gelation time is therefore defined as thetime point at which a large increase in solution viscosity occurs. Inorder to measure the onset time, 125 ml of solution prepared at 85° C.was placed in a 150 ml narrow beaker. The beaker was placed in a roomtemperature water bath which was positioned centrally under a BrookfieldDVI-I⁺ viscometer fitted with a S62 spindle. The solution viscosity wasmeasured at 10 rpm; every 5-10 minutes (or more frequent if needed), ameasurement was taken by averaging the viscosity over a 60 secondinterval. The resulting data is plotted and the onset time can bedetermined either graphically or by curve fitting methods.

A summary of the gelation times of some of the polymers of the presentinvention as well as some controls can be found in Table 4. Control1-Random is a 64/36 random copolymer of glycolide and caprolactone, madeby placing all of the reactants in the reactor at the start of theco-polymerization. Control 1-Block a 64/36 segmented block copolymer ofglycolide and caprolactone, made by the process of sequential additionof monomers. Control 2-Block is similar to Control 1-Block with theexception of overall composition; it is a 75/25 segmented blockcopolymer of glycolide and caprolactone.

TABLE 4 Gelation Time of Polymers of the Present Invention and ControlsMax. Gelation time Composition Concentration at 10 wt %, Example (mole%) (wt. %) (min) 1 64/36 Lac/Cap 30% >2880 2A 72/28 Lac/Cap 20% >2880 3A74/26 Lac/Cap 15% >180 Control 1- 64/36 Gly/Cap 24% >180 but Random<1440 Control 1- 64/36 Gly/Cap 14% 14 Block Control 2- 75/25 Gly/Cap<0.5%   Insoluble Block

Example 12

Subjective In Vitro Degradation Behavior of Foams from Examples 7, 8,and 9

The degradation behavior of all four foams from Examples 7, 8, and 9were evaluated by assessing the integrity of the foams when exposed to adegradation media over time. Briefly, a single foam strip was placed ina 50 ml conical tube and immersed in 50 ml of a pH 7.27 phosphatebuffered solution. The tube was then placed on a shaker table in acontrolled environmental chamber at 37° C. The selected test conditionsusually mimic what may occur in an in vivo environment. The shaker tableprovided gentle agitation throughout the duration of the study. Foamsamples were examined periodically for structural integrity byaggressively shaking the tube imparting turbulence to the sample. Thenumber of days submerged in buffer at 37° C. until the sample broke wasrecorded. This test was repeated three times for each foam. The resultsare presented in FIGS. 3A to 6C.

As a comparator, foam of a random copolymer of 36/64 caprolactone andglycolide (CAP/GLY) was prepared in an identical fashion as described inthe foam preparation methods of Examples 7, 8, and 9 and subjected tothe same test conditions as described above. FIG. 7A is a photograph ofthree foam strips from 36/64 Caprolactone and Glycolide Comparator madeby 10% w/w concentration of solids prior to exposure to a pH 7.27phosphate buffered solution at 37° C.

All foam samples, comparative and inventive, maintained integrity up to24 days. On day 25, one of the foam strips made from the comparative36/64 CAP/GLY random copolymer broke upon agitation of the tube. By day28, the remaining two foams of this comparative 36/64 CAP/GLY randomcopolymer had fragmented as well; this is shown in the photograph inFIG. 7B. By day 64, the foam strips of the comparative 36/64 CAP/GLYrandom copolymer had extensively fragmented; this is shown in thephotograph in FIG. 7C.

In contrast, all foams of the inventive segmentedpoly(L(−)-lactide-co-epsilon-caprolactone) block copolymers hadmaintained integrity through 28 days as shown in FIGS. 3B, 4B, 5B, and6B.

The study was continued to 64 days where the foams of the inventivesegmented poly(L(−)-lactide-co-epsilon-caprolactone) block copolymersmaintained integrity. This is shown in the photographs in FIGS. 3C, 4C,5C, and 6C. The test articles were removed from the buffer and handledwith forceps without any breakage. While there was no directmeasurement, there were no apparent changes in the dimensions of thesefoams. Again in contrast, the foam strips of the comparative 36/64CAP/GLY random copolymer has been completely disrupted at 64 days (seeFIG. 7C).

Finally, examples of absorbable polymer solutions that failed tolyophilize into acceptable foams are shown in the bottom article in FIG.8 and the article of FIG. 9. These foams were made from a solutionhaving 10 weight percent of the 36/64 Caprolactone and Glycolidecopolymer having endblocks as described in Donners et al. The top foamin FIG. 8 was made using lyophilization with a “quench” freeze, in whichthe solution was cooled quickly before a gel can form. The bottom foamin FIG. 8 was made without the quench step, which resulted in a failedfoam that had high residual 1,4-dioxane levels, and had a warped“potato-chip” like appearance. Similarly, FIG. 9 shows failed foam ofthe same material prepared as a 4×4 inch sheet. The procedure also didnot include a “quench” freeze step, which as shown in Donners et al., isneeded for the lyophilization of polymer solutions that exhibit gelformation but not needed for the polymers of the present invention.

Example 13 Film Formation by Melt Extrusion of the Resin of Example 2A

a) Melt Extrusion

The melt film extrusion of the resin of Example 2A of the presentinvention was carried out using a melt extruder Model KN125 manufacturedby Davis Standard Corp., Pawcatuck, CT 06379, U.S.A, outfitted with afilm die. A die gap of 6 mils was used in all film extrusion runs.Extruder temperatures throughout the different barrel zones ranged from160 to 190° C., with the die temperature kept at 190° C. The screw speedwas set to 10.9 rpm, while the linear speed of the pull out roll wasmaintained at 4.9 fpm. During film collection, a silicone release paperdispensed from a roll stand was used to separate the film layers beingwound on the take-up roll. After extrusion, the film with correspondingsilicone release paper was unrolled and cut to convenient lengths. Thecut films were then stored under vacuum, sandwiched between siliconerelease paper, prior to further use. The thickness of the film wasdetermined to be 3.0 mil.

b) Post-Treatment—Annealing

The extruded film of the resin of Example 2A of the present inventionwas additionally heat treated to mature the polymer morphology and toaid in the removal of any residual monomer regenerated during the meltprocessing. The thermal treatment (annealing) was found to increase thecrystallinity level, which is then expected to improve the dimensionalstability of the film samples. Annealing was conducted under nitrogenusing a Thermal Product Solutions (TPS) Blue M heating oven (Model No.:DCI-336-C-MP550), White Deer, Pa., U.S.A. After purging with nitrogen,the annealing temperature was initially kept at 60° C. for two hours,followed by 100° C. for an additional 6 hours. After annealing, thecooled films were stored under vacuum until further testing. Heattreatments (annealing) are advantageously conducted under an inertatmosphere to minimize unwanted hydrolysis and/or oxidation.

Example 14 Film Formation by Melt Extrusion of the Resin of Example 3B

a) Melt Extrusion

The melt film extrusion of the resin of Example 3B was conducted in asimilar fashion as described in Example 13 above. For this resin, theextruder temperatures were slightly higher due to the slightly highermolecular weight resulting in a slightly higher melt viscosity of theExample 3B resin. Throughout the different barrel zones, the temperatureranged from 160° C. to 200° C., with the die temperature kept at 200° C.A screw speed of 14.0 rpm was used, while the linear speed of the pullout roll was maintained at 5.0 fpm. During film collection, a siliconerelease paper dispensed from a roll stand was used to separate the filmlayers being wound on the take-up roll. After extrusion, the film withcorresponding silicone release paper was unrolled and cut to convenientlengths. The cut films were then stored under vacuum, sandwiched betweensilicone release paper, prior to further use. The thickness of the filmwas also 3.0 mil.

b) Post-Treatment—Annealing

The annealing of the films of Example 14 prepared using the resin ofExample 3B of the present invention was conducted using identicalconditions to those described in Example 13 above.

Example 15 Subjective Mechanical Property Description

Both annealed films of Examples 13 and 14 were colorless, smooth,pliable, yet not tacky. Upon extensive physical treatments, includingrepeated bending procedures, pulling and other subjective handlingoperations, the films did not tear or showed any sign of damage.

Example 16 Thermal Analysis Before and After Annealing

Differential Scanning calorimetry (DSC) measurements were conductedusing a Model Q20-3290 calorimeter from TA Instruments (New Castle,Del.) equipped with an automatic sampler. In individual experiments,between 5 and 10 mg samples of the 3-mil polymer films, unannealed orheat treated (annealed), as described in Examples 13 and 14, were placedinto DSC pans, quenched below −60° C., and heated at the constantheating rate of 10° C./min to determine their calorimetric properties(first heat properties); these included the glass transitiontemperature, T_(g), the crystallization temperature, T_(c), the heat ofcrystallization, ΔH_(c), the melting point, T_(m) and the heat offusion, ΔH_(m). The films were subsequently melted at 200° C. and thenquenched below −60° C. to collect “Second Heat” data. From the secondheat measurements values for T_(g), T_(m), T_(c) (crystallizationtemperature), ΔH_(c), and ΔH_(m) were obtained that are independent fromthe samples previous heat treatment history. Data obtained usingcalorimetry measurements are summarized in Table 5.

TABLE 5 Thermal (Calorimetric) Properties of Unannealed and Annealed3-mil Extruded Films First heat Second heat* T_(C) T_(C) T_(g) (°C.)/ΔH_(C) T_(m) ΔH_(m) % T_(g) (° C.)/ΔH_(C) T_(m) ΔH_(m) Film ID (°C.) (J/g) (° C.) (J/g) Cryst.** (° C.) (J/g) (° C.) (J/g) Example 13-15.4 76.8/21.0 165.6 26.4 28% 25.0 114.6/25.8 166.3 26.3 UnannealExample 13- −3.0 none 166.6 28.9 31% 26.0 112.4/25.7 167.1 27.0 AnnealedExample 14- 45.0 86.0/24.3 166.5 27.3 29% 52.5 117.4/29.0 167.5 29.5Unanneal Example 14- −30.0 none 167.0 34.0 36% 53.2 116.3/30.1 167.730.6 Annealed *The second heat DSC measurements for the films of thepresent invention were started by melting the resin at 200° C. for 2minutes, with a subsequent quench (−60° C./min) to −10° C., followed bythe constant heating scan at 10° C./min. **Based on the heat of fusionof 100 PLLA resin = 93.7 J/g.

Annealed films of the present invention exhibit low glass transitiontemperatures (below 0° C.). The exemplary films of Examples 13 and 14exhibited levels of crystallinity of 31% and 36%, respectively, whichhelped enable the films to be dimensionally stable, strong, yet soft,for superb handling. It is expected that the films of the presentinvention will display crystallinity levels, once annealed, betweenabout 25 percent and 40 percent.

Although this invention has been shown and described with respect todetailed embodiments thereof, it will be understood by those skilled inthe art that various changes in form and detail thereof may be madewithout departing from the spirit and scope of the claimed invention.

We claim: 1-12. (canceled)
 13. A method of making an absorbable foam bya lyophilization process, comprising the steps of: A. providing anabsorbable polymer comprising a semicrystalline absorbable segmentedcopolymer, said copolymer comprising repeating units of polymerizedlactide and polymerized epsilon-caprolactone, wherein the mole ratio ofpolymerized lactide to polymerized epsilon-caprolactone is between about60:40 to about 75:25, said copolymer having a first heat Tg, asdetermined by differential scanning calorimetry at a scan rate of 10° C.per minute, equal to or less than 0° C., and a crystallinity level ofabout 20 to about 50 percent, as measured by wide angle X-raydiffraction; B. dissolving a sufficient quantity of the copolymer in asuitable solvent to form a lyophilizing solution; C. pouring at least apart of the solution into a suitable mold; and, D. subjecting thesolution in the mold to a lyophilizing process to form an absorbablefoam.
 14. The method of claim 13 wherein the solvent is selected fromthe group consisting of 1,4-dioxane, trioxane, a mixture of at least 90weight percent 1,4-dioxane and no more than 10 weight percent water, anda mixture of at least 90 weight percent 1,4-dioxane and no more than 10weight percent of an organic alcohol having a molecular weight of lessthan 1500 Daltons.
 15. The method of claim 13 wherein the dissolvedabsorbable polymer is between about 3 to about 30 percent by weight ofthe solution.
 16. The method of claim 13 wherein the resulting foam hasa thickness between about 20 to about 500 mils.
 17. A lyophilizingsolution, comprising: A. a solvent selected from the group consisting of1,4-dioxane, trioxane, a mixture of at least 90 weight percent1,4-dioxane and no more than 10 weight percent water, and a mixture ofat least 90 weight percent 1,4-dioxane and no more than 10 weightpercent of an organic alcohol having a molecular weight of less than1500 Daltons; and, B. about 3 wt. % to about 30 wt. % of a polymercomprising a semicrystalline absorbable segmented copolymer, thecopolymer comprising repeating units of polymerized lactide andpolymerized epsilon-caprolactone, wherein the mole ratio of polymerizedlactide to polymerized epsilon-caprolactone is between about 60:40 toabout 75:25, said copolymer having a first heat Tg, as determined bydifferential scanning calorimetry at a scan rate of 10° C. per minute,equal to or less than 0° C., and a crystallinity level of about 20 toabout 50 percent, as measured by wide angle X-ray diffraction.
 18. Thelyophilizing solution of claim 17 wherein said solution remainsnon-gelling at 20° C. for at least 18 hours.
 19. The lyophilizingsolution of claim 17 wherein said solution remains non-gelling at 20° C.for at least 168 hours. 20-25. (canceled)